Publications by authors named "Isabelle Schrauwen"

77 Publications

Bi-Allelic Novel Variants in Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment.

Authors:
Edmond Wonkam-Tingang Isabelle Schrauwen Kevin K Esoh Thashi Bharadwaj Liz M Nouel-Saied Anushree Acharya Abdul Nasir Samuel M Adadey Shaheen Mowla Suzanne M Leal Ambroise Wonkam

Genes (Basel) 2020 Oct 23;11(11). Epub 2020 Oct 23.

Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.

DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in . The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant -p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant -(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe involvement in human hearing impairment, and thus confirms as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.
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http://dx.doi.org/10.3390/genes11111249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690789PMC
October 2020

Splicing Characteristics of Dystrophin Pseudoexons and Identification of a Novel Pathogenic Intronic Variant in the Gene.

Authors:
Zhiying Xie Liuqin Tang Zhihao Xie Chengyue Sun Haoyue Shuai Chao Zhou Yilin Liu Meng Yu Yiming Zheng Lingchao Meng Wei Zhang Suzanne M Leal Zhaoxia Wang Isabelle Schrauwen Yun Yuan

Genes (Basel) 2020 Oct 10;11(10). Epub 2020 Oct 10.

Department of Neurology, Peking University First Hospital, Beijing 100034, China.

Pseudoexon (PE) inclusion has been implicated in various dystrophinopathies; however, its splicing characteristics have not been fully investigated. This study aims to analyze the splicing characteristics of dystrophin PEs and compare them with those of dystrophin canonical exons (CEs). Forty-two reported dystrophin PEs were divided into a splice site (ss) group and a splicing regulatory element (SRE) group. Five dystrophin PEs with characteristics of poison exons were identified and categorized as the possible poison exon group. The comparative analysis of each essential splicing signal among different groups of dystrophin PEs and dystrophin CEs revealed that the possible poison exon group had a stronger 3' ss compared to any other group. As for auxiliary SREs, different groups of dystrophin PEs were found to have a smaller density of diverse types of exonic splicing enhancers and a higher density of several types of exonic splicing silencers compared to dystrophin CEs. In addition, the possible poison exon group had a smaller density of 3' ss intronic splicing silencers compared to dystrophin CEs. To our knowledge, our findings indicate for the first time that poison exons might exist in (the dystrophin gene) and present with different splicing characteristics than other dystrophin PEs and CEs.
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http://dx.doi.org/10.3390/genes11101180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650627PMC
October 2020

Practical approach to the genetic diagnosis of unsolved dystrophinopathies: a stepwise strategy in the genomic era.

Authors:
Zhiying Xie Chengyue Sun Yilin Liu Meng Yu Yiming Zheng Lingchao Meng Gao Wang Diana M Cornejo-Sanchez Thashi Bharadwaj Jin Yan Lingxiang Zhang Nicolas Pineda-Trujillo Wei Zhang Suzanne M Leal Isabelle Schrauwen Zhaoxia Wang Yun Yuan

J Med Genet 2020 Sep 25. Epub 2020 Sep 25.

Department of Neurology, Peking University First Hospital, Beijing, China

Objective: To investigate the diagnostic value of implementing a stepwise genetic testing strategy (SGTS) in genetically unsolved cases with dystrophinopathies.

Methods: After routine genetic testing in 872 male patients with highly suspected dystrophinopathies, we identified 715 patients with a pathogenic variant. Of the 157 patients who had no pathogenic variants and underwent a muscle biopsy, 142 patients were confirmed to have other myopathies, and 15 suspected dystrophinopathies remained genetically undiagnosed. These 15 patients underwent a more comprehensive evaluation as part of the SGTS pipeline, which included the stepwise analysis of dystrophin mRNA, short-read whole-gene sequencing, long-read whole-gene sequencing and bioinformatic analyses.

Results: SGTS successfully yielded a molecular diagnosis of dystrophinopathy in 11 of the 15 genetically unsolved cases. We identified 8 intronic and 2 complex structural variants (SVs) leading to aberrant splicing in 10 of 11 patients, of which 9 variants were novel. In one case, a molecular defect was detected on mRNA and protein level only. Aberrant splicing mechanisms included 6 pseudoexon inclusions and 4 alterations of splice sites and splicing regulatory elements. We showed for the first time the exonisation of a MER48 element as a novel pathogenic mechanism in dystrophinopathies.

Conclusion: Our study highlights the high diagnostic utility of implementing a SGTS pipeline in dystrophinopathies with intronic variants and complex SVs.
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http://dx.doi.org/10.1136/jmedgenet-2020-107113DOI Listing
September 2020

Long-read whole-genome sequencing for the genetic diagnosis of dystrophinopathies.

Authors:
Zhiying Xie Chengyue Sun Siwen Zhang Yilin Liu Meng Yu Yiming Zheng Lingchao Meng Anushree Acharya Diana M Cornejo-Sanchez Gao Wang Wei Zhang Isabelle Schrauwen Suzanne M Leal Zhaoxia Wang Yun Yuan

Ann Clin Transl Neurol 2020 10 20;7(10):2041-2046. Epub 2020 Sep 20.

Department of Neurology, Peking University First Hospital, Beijing, 100034, China.

The precise genetic diagnosis of dystrophinopathies can be challenging, largely due to rare deep intronic variants and more complex structural variants (SVs). We report on the genetic characterization of a dystrophinopathy patient. He remained without a genetic diagnosis after routine genetic testing, dystrophin protein and mRNA analysis, and short- and long-read whole DMD gene sequencing. We finally identified a novel complex SV in DMD via long-read whole-genome sequencing. The variant consists of a large-scale (~1Mb) inversion/deletion-insertion rearrangement mediated by LINE-1s. Our study shows that long-read whole-genome sequencing can serve as a clinical diagnostic tool for genetically unsolved dystrophinopathies.
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http://dx.doi.org/10.1002/acn3.51201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545597PMC
October 2020

Congenital myasthenic syndrome caused by a frameshift insertion mutation in .

Authors:
Szabolcs Szelinger Jonida Krate Keri Ramsey Samuel P Strom Perry B Shieh Hane Lee Newell Belnap Chris Balak Ashley L Siniard Megan Russell Ryan Richholt Matt De Both Ana M Claasen Isabelle Schrauwen Stanley F Nelson Matthew J Huentelman David W Craig Samuel P Yang Steven A Moore Kumaraswamy Sivakumar Vinodh Narayanan Sampathkumar Rangasamy

Neurol Genet 2020 Aug 30;6(4):e468. Epub 2020 Jun 30.

theNeurogenomics Division (S.S., J.K., K.R., N.B., C.B., A.L.S., M.R., R.R., M.D.B., A.M.C., M.J.H, V.N., S.R.), Translational Genomics Research Institute, Center for Rare Childhood Disorders, Phoenix, AZ; Fulgent Genetics (S.P.S.), Temple City, CA; Department of Neurology (P.B.S.), University of California Los Angeles; David Geffen School of Medicine (P.B.S.), Los Angeles; Department of Pathology and Laboratory Medicine (H.L., S.F.N.), University of California, Los Angeles; Department of Human Genetics (H.L., S.F.N.), David Geffen School of Medicine; Department of Neurology (I.S.), Columbia University, Center for Statistical Genetics, New York; Department of Translational Genomics (D.W.C.), University of Southern California, Los Angeles; Providence Sacred Heart Medical Center and Children's Hospital (S.P.Y.), Spokane, WA; Department of Pathology (S.A.M), University of Iowa, Carver College of Medicine; and Neuromuscular Clinic and Research Center (K.S.), Phoenix, AZ.

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 () gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.

Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed.

Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.

Conclusions: These results expand on the spectrum of known loss-of-function mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.
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http://dx.doi.org/10.1212/NXG.0000000000000468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357421PMC
August 2020

Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment.

Authors:
Isabelle Schrauwen Khurram Liaqat Isabelle Schatteman Thashi Bharadwaj Abdul Nasir Anushree Acharya Wasim Ahmad Guy Van Camp Suzanne M Leal

Genes (Basel) 2020 06 23;11(6). Epub 2020 Jun 23.

Center for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer's Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in , a neural crest regulatory molecule. The p.(Thr116Ile) variant was also associated with bilateral cochlear aplasia and cochlear nerve aplasia upon temporal bone imaging, an ultra-rare phenotype previously seen in patients with de novo variants. An important role of GREB1L in normal ear development has also been demonstrated by zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in , as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with variants and strengthen the evidence of the involvement of in human hearing.
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http://dx.doi.org/10.3390/genes11060687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349314PMC
June 2020

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease.

Authors:
Ignazio S Piras Christiane Bleul Isabelle Schrauwen Joshua Talboom Lorida Llaci Matthew D De Both Marcus A Naymik Glenda Halliday Conceicao Bettencourt Janice L Holton Geidy E Serrano Lucia I Sue Thomas G Beach Nadia Stefanova Matthew J Huentelman

Acta Neuropathol Commun 2020 06 3;8(1):76. Epub 2020 Jun 3.

Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and PSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.
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http://dx.doi.org/10.1186/s40478-020-00950-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268362PMC
June 2020

Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings.

Authors:
Renata Szalai Bela I Melegh Agnes Till Reka Ripszam Gyorgyi Csabi Anushree Acharya Isabelle Schrauwen Suzanne M Leal Samuel Komoly Gyorgy Kosztolanyi Kinga Hadzsiev

Exp Mol Pathol 2020 08 21;115:104471. Epub 2020 May 21.

University of Pecs, Medical School, Department of Medical Genetics, Pecs, Hungary; Szentagothai Research Center, University of Pecs, Pecs, Hungary.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.
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http://dx.doi.org/10.1016/j.yexmp.2020.104471DOI Listing
August 2020

ESHRD: deconvolution of brain homogenate RNA expression data to identify cell-type-specific alterations in Alzheimer's disease.

Authors:
Ignazio S Piras Christiane Bleul Joshua S Talboom Matthew D De Both Isabelle Schrauwen Glenda Halliday Amanda J Myers Geidy E Serrano Thomas G Beach Matthew J Huentelman

Aging (Albany NY) 2020 03 2;12(5):4124-4162. Epub 2020 Mar 2.

Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA.

Objective: We describe herein a bioinformatics approach that leverages gene expression data from brain homogenates to derive cell-type specific differential expression results.

Results: We found that differentially expressed (DE) cell-specific genes were mostly identified as neuronal, microglial, or endothelial in origin. However, a large proportion (75.7%) was not attributable to specific cells due to the heterogeneity in expression among brain cell types. Neuronal DE genes were consistently downregulated and associated with synaptic and neuronal processes as described previously in the field thereby validating this approach. We detected several DE genes related to angiogenesis (endothelial cells) and proteoglycans (oligodendrocytes).

Conclusions: We present a cost- and time-effective method exploiting brain homogenate DE data to obtain insights about cell-specific expression. Using this approach we identify novel findings in AD in endothelial cells and oligodendrocytes that were previously not reported.

Methods: We derived an enrichment score for each gene using a publicly available RNA profiling database generated from seven different cell types isolated from mouse cerebral cortex. We then classified the differential expression results from 3 publicly accessible Late-Onset Alzheimer's disease (AD) studies including seven different brain regions.
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http://dx.doi.org/10.18632/aging.102840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093163PMC
March 2020

Genes Implicated in Rare Congenital Inner Ear and Cochleovestibular Nerve Malformations.

Authors:
Elina Kari Lorida Llaci John L Go Marcus Naymik James A Knowles Suzanne M Leal Sampath Rangasamy Matthew J Huentelman Winnie Liang Rick A Friedman Isabelle Schrauwen

Ear Hear 2020 Jul/Aug;41(4):983-989

Neurogenomics Division and Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, USA.

Objective: A small subset of children with congenital hearing loss have abnormal cochleovestibular nerves (i.e., absent, aplastic, or deficient cochlear nerves), with largely unknown etiology. Our objective was to investigate the underlying pathways and identify novel genetic variants responsible for cochleovestibular malformations and nerve abnormalities. It is our hypothesis that several cochleovestibular nerve abnormalities might share common causative pathways.

Design: We used a family-based exome sequencing approach to study 12 children with known rare inner ear and/or cochleovestibular nerve malformations.

Results: Our results highlight a diverse molecular etiology and suggest that genes important in the developing otic vesicle and cranial neural crest, e.g., MASP1, GREB1L, SIX1, TAF1, are likely to underlie inner ear and/or cochleovestibular nerve malformations.

Conclusions: We show that several cochleovestibular nerve malformations are neurocristopathies, which is consistent with the fact that cochleovestibular nerve development is based on otic placode-derived neurons in close association with neural crest-derived glia cells. In addition, we suggest potential genetic markers for more severely affected phenotypes, which may help prognosticate individual cochlear implantation outcomes. Developing better strategies for identifying which children with abnormal nerves will benefit from a cochlear implantation is crucial, as outcomes are usually far less robust and extremely variable in this population, and current neuroimaging and electrophysiologic parameters cannot accurately predict outcomes. Identification of a suitable treatment early will reduce the use of multiple interventions during the time-sensitive period for language development.
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http://dx.doi.org/10.1097/AUD.0000000000000819DOI Listing
January 2020

Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD).

Authors:
Lorida Llaci Keri Ramsey Newell Belnap Ana M Claasen Chris D Balak Szabolcs Szelinger Wayne M Jepsen Ashley L Siniard Ryan Richholt Tyler Izat Marcus Naymik Matt De Both Ignazio S Piras David W Craig Matthew J Huentelman Vinodh Narayanan Isabelle Schrauwen Sampathkumar Rangasamy

Hum Genet 2019 Dec 20;138(11-12):1409-1417. Epub 2019 Nov 20.

Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient's blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.
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http://dx.doi.org/10.1007/s00439-019-02077-7DOI Listing
December 2019

Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia.

Authors:
Carmel G McCullough Szabolcs Szelinger Newell Belnap Keri Ramsey Isabelle Schrauwen Ana M Claasen Leah W Burke Ashley L Siniard Matthew J Huentelman Vinodh Narayanan David W Craig

Hum Mutat 2020 02 14;41(2):412-419. Epub 2019 Nov 14.

Department of Translational Genomics, University of Southern California, Los Angeles, California.

We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.
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http://dx.doi.org/10.1002/humu.23939DOI Listing
February 2020

Further evidence of involvement of TMEM132E in autosomal recessive nonsyndromic hearing impairment.

Authors:
Khurram Liaqat Shabir Hussain Muhammad Bilal Abdul Nasir Anushree Acharya Raja Hussain Ali Shoaib Nawaz Muhammad Umair Isabelle Schrauwen Wasim Ahmad Suzanne M Leal

J Hum Genet 2020 Jan 28;65(2):187-192. Epub 2019 Oct 28.

Center of Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Autosomal-recessive (AR) nonsyndromic hearing impairment (NSHI) displays a high degree of genetic heterogeneity with >100 genes identified. Recently, TMEM132E, which is highly expressed in inner hair cells, was suggested as a novel ARNSHI gene for DFNB99. A missense variant c.1259G>A: p.(Arg420Gln) in TMEM132E was identified that segregated with ARNSHI in a single Chinese family with two affected members. In the present study, a family of Pakistani origin with prelingual profound sensorineural hearing impairment displaying AR mode of inheritance was investigated via exome and Sanger sequencing. Compound heterozygous variants c.382G>T: p.(Ala128Ser) and c.2204C>T: p.(Pro735Leu) in TMEM132E were observed in affected but not in unaffected family members. TMEM132E variants identified in this and the previously reported ARNSHI family are located in the extracellular domain. In conclusion, we present a second ARNSHI family with TMEM132E variants which strengthens the evidence of the involvement of this gene in the etiology of ARNSHI.
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http://dx.doi.org/10.1038/s10038-019-0691-4DOI Listing
January 2020

A de novo SIX1 variant in a patient with a rare nonsyndromic cochleovestibular nerve abnormality, cochlear hypoplasia, and bilateral sensorineural hearing loss.

Authors:
Elina Kari Lorida Llaci John L Go Marcus Naymik James A Knowles Suzanne M Leal Sampath Rangasamy Matthew J Huentelman Rick A Friedman Isabelle Schrauwen

Mol Genet Genomic Med 2019 12 8;7(12):e995. Epub 2019 Oct 8.

Neurogenomics Division and Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.

Background: Childhood hearing impairment affects language and cognitive development. Profound congenital sensorineural hearing impairment can be due to an abnormal cochleovestibular nerve (CVN) and cochleovestibular malformations, however, the etiology of these conditions remains unclear.

Methods: We used a trio-based exome sequencing approach to unravel the underlying molecular etiology of a child with a rare nonsyndromic CVN abnormality and cochlear hypoplasia. Clinical and imaging data were also reviewed.

Results: We identified a de novo missense variant [p(Asn174Tyr)] in the DNA-binding Homeodomain of SIX1, a gene which previously has been associated with autosomal dominant hearing loss (ADHL) and branchio-oto-renal or Branchio-otic syndrome, a condition not seen in this patient.

Conclusions: SIX1 has an important function in otic vesicle patterning during embryogenesis, and mice show several abnormalities to their inner ear including loss of inner ear innervation. Previous reports on patients with SIX1 variants lack imaging data and nonsyndromic AD cases were reported to have no inner ear malformations. In conclusion, we show that a de novo variant in SIX1 in a patient with sensorineural hearing loss leads to cochleovestibular malformations and abnormalities of the CVN, without any other abnormalities. Without proper interventions, severe to profound hearing loss is devastating to both education and social integration. Choosing the correct intervention can be challenging and a molecular diagnosis may adjust intervention and improve outcomes, especially for rare cases.
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http://dx.doi.org/10.1002/mgg3.995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900394PMC
December 2019

A Start Codon Variant in Underlies Symphalangism and Ossicular Chain Malformations Affecting Both the Incus and the Stapes.

Authors:
Nathan R Lindquist Eric N Appelbaum Anushree Acharya Jeffrey T Vrabec Suzanne M Leal Isabelle Schrauwen

Case Rep Genet 2019 22;2019:2836263. Epub 2019 Jul 22.

Center for Statistical Genetics, Department of Neurology, Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA.

We performed exome sequencing to evaluate the underlying molecular cause of a patient with bilateral conductive hearing loss due to multiple ossicular abnormalities as well as symphalangism of the fifth digits. This leads to the identification of a novel heterozygous start codon variant in the gene (c.2T>C:p.Met1?) that hinders normal translation of the noggin protein. Variants in lead to a spectrum of otologic, digit, and joint abnormalities, a combination suggested to be referred to as -related-symphalangism spectrum disorder (-SSD). Conductive hearing loss from such variants may stem from stapes footplate ankylosis, fixation of the malleoincudal joint, or fixation of the incus short process. In this case, the constellation of both stapes and incus fixation, an exceptionally tall stapes suprastructure, thickened long process of the incus, and enlarged incus body was encountered, leading to distinct challenges during otologic surgery to improve hearing thresholds. This case highlights multiple abnormalities to the ossicular chain in a patient with a start codon variant in . We provide detailed imaging data on these malformations as well as surgical considerations and outcomes.
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http://dx.doi.org/10.1155/2019/2836263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679842PMC
July 2019

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors.

Authors:
Joshua S Talboom Asta Håberg Matthew D De Both Marcus A Naymik Isabelle Schrauwen Candace R Lewis Stacy F Bertinelli Callie Hammersland Mason A Fritz Amanda J Myers Meredith Hay Carol A Barnes Elizabeth Glisky Lee Ryan Matthew J Huentelman

Elife 2019 06 18;8. Epub 2019 Jun 18.

The Translational Genomics Research Institute, Phoenix, United States.

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.
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http://dx.doi.org/10.7554/eLife.46179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615857PMC
June 2019

Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry.

Authors:
Imen Chakchouk Di Zhang Zhihui Zhang Laurent C Francioli Regie Lyn P Santos-Cortez Isabelle Schrauwen Suzanne M Leal

Eur J Hum Genet 2019 09 3;27(9):1456-1465. Epub 2019 May 3.

Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Hearing impairment (HI) is characterized by extensive genetic heterogeneity. To determine the population-specific contribution of known autosomal recessive nonsyndromic (ARNS)HI genes and variants to HI etiology; pathogenic and likely pathogenic (PLP) ARNSHI variants were selected from ClinVar and the Deafness Variation Database and their frequencies were obtained from gnomAD for seven populations. ARNSHI prevalence due to PLP variants varies greatly by population ranging from 96.9 affected per 100,000 individuals for Ashkenazi Jews to 5.2 affected per 100,000 individuals for Africans/African Americans. For Europeans, Finns have the lowest prevalence due to ARNSHI PLP variants with 9.5 affected per 100,000 individuals. For East Asians, Latinos, non-Finish Europeans, and South Asians, ARNSHI prevalence due to PLP variants ranges from 17.1 to 33.7 affected per 100,000 individuals. ARNSHI variants that were previously reported in a single ancestry or family were observed in additional populations, e.g., USH1C p.(Q723*) reported in a Chinese family was the most prevalent pathogenic variant observed in gnomAD for African/African Americans. Variability between populations is due to how extensively ARNSHI has been studied, ARNSHI prevalence and ancestry specific ARNSHI variant architecture which is impacted by population history. Our study demonstrates that additional gene and variant discovery studies are necessary for all populations and particularly for individuals of African ancestry.
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http://dx.doi.org/10.1038/s41431-019-0417-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777454PMC
September 2019

Heterozygosity mapping for human dominant trait variants.

Authors:
Atsuko Imai-Okazaki Yi Li Sukanya Horpaopan Yasser Riazalhosseini Masoud Garshasbi Yael P Mosse Di Zhang Isabelle Schrauwen Aarushi Sharma Cathy S J Fann Suzanne M Leal Mark Lathrop Jurg Ott

Hum Mutat 2019 07 24;40(7):996-1004. Epub 2019 Apr 24.

Laboratory of Statistical Genetics, Rockefeller University, New York, New York.

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.
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http://dx.doi.org/10.1002/humu.23765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617796PMC
July 2019

Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly.

Authors:
Irfan Ullah Naseebullah Kakar Isabelle Schrauwen Shabir Hussain Imen Chakchouk Khurram Liaqat Anushree Acharya Naveed Wasif Regie Lyn P Santos-Cortez Saadullah Khan Abdul Aziz Kwanghyuk Lee Julien Couthouis Denise Horn Bjørt K Kragesteen Malte Spielmann Holger Thiele Deborah A Nickerson Michael J Bamshad Aaron D Gitler Jamil Ahmad Muhammad Ansar Guntram Borck Wasim Ahmad Suzanne M Leal

Hum Genet 2019 Jun 13;138(6):593-600. Epub 2019 Apr 13.

Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA.

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.
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http://dx.doi.org/10.1007/s00439-019-02000-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724712PMC
June 2019

Insufficient evidence for a role of SERPINF1 in otosclerosis.

Authors:
Hanne Valgaeren Manou Sommen Matthias Beyens Geert Vandeweyer Isabelle Schrauwen Anne Schepers Isabelle Schatteman Vedat Topsakal Ingeborg Dhooge Henricus Kunst Diego Zanetti Alexander M Huber Alexander Hoischen Erik Fransen Guy Van Camp

Mol Genet Genomics 2019 Aug 9;294(4):1001-1006. Epub 2019 Apr 9.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, Wilrijk, 2610, Antwerp, Belgium.

Otosclerosis is a common form of hearing loss (HL) due to abnormal remodeling of the otic capsule. The genetic causes of otosclerosis remain largely unidentified. Only mutations in a single gene, SERPINF1, were previously published in patients with familial otosclerosis. To unravel the contribution of genetic variation in this gene to otosclerosis, this gene was re-sequenced in a large population of otosclerosis patients and controls. Resequencing of the 5' and 3' UTRs, coding regions, and exon-intron boundaries of SERPINF1 was performed in 1604 unrelated otosclerosis patients and 1538 unscreened controls, and in 62 large otosclerosis families. Our study showed no enrichment of rare variants, stratified by type, in SERPINF1 in patients versus controls. Furthermore, the c.392C > A (p.Ala131Asp) variant, previously reported as pathogenic, was identified in three patients and four controls, not replicating its pathogenic nature. We could also not find evidence for a pathogenic role in otosclerosis for 5' UTR variants in the SERPINF1-012 transcript (ENST00000573763), described as the major transcript in human stapes. Furthermore, no rare variants were identified in the otosclerosis families. This study does not support a pathogenic role for variants in SERPINF1 as a cause of otosclerosis. Therefore, the etiology of the disease remains largely unknown and will undoubtedly be the focus of future studies.
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http://dx.doi.org/10.1007/s00438-019-01558-8DOI Listing
August 2019

Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects.

Authors:
Beate Peter Valentin Dinu Li Liu Matthew Huentelman Marcus Naymik Hope Lancaster Caitlin Vose Isabelle Schrauwen

Behav Genet 2019 07 4;49(4):399-414. Epub 2019 Apr 4.

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.

Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.
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http://dx.doi.org/10.1007/s10519-019-09957-8DOI Listing
July 2019

Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma.

Authors:
Isabelle Schrauwen Béla I Melegh Imen Chakchouk Anushree Acharya Abdul Nasir Alexis Poston Diana M Cornejo-Sanchez Zsolt Szabo Tamás Karosi Judit Bene Béla Melegh Suzanne M Leal

Eur J Hum Genet 2019 06 14;27(6):869-878. Epub 2019 Mar 14.

Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, USA.

Roma are a socially and culturally distinct isolated population with genetically divergent subisolates, residing mainly across Central, Southern, and Eastern Europe. We evaluated the genetic etiology of hearing impairment (HI) in 15 Hungarian Roma families through exome sequencing. A family with autosomal dominant non-syndromic HI segregating a rare variant in the Calponin-homology 2 domain of PLS1, or Plastin 1 [p.(Leu363Phe)] was identified. Young adult Pls1 knockout mice have progressive HI and show morphological defects to their inner hair cells. There is evidence that PLS1 is important in the preservation of adult stereocilia and normal hearing. Four families segregated the European ancestral variant c.35delG [p.(Gly12fs)] in GJB2, and one family was homozygous for p.(Trp24*), an Indian subcontinent ancestral variant which is common amongst Roma from Slovakia, Czech Republic, and Spain. We also observed variants in known HI genes USH1G, USH2A, MYH9, MYO7A, and a splice site variant in MANBA (c.2158-2A>G) in a family with HI, intellectual disability, behavioral problems, and respiratory inflammation, which was previously reported in a Czech Roma family with similar features. Lastly, using multidimensional scaling and ADMIXTURE analyses, we delineate the degree of Asian/European admixture in the HI families understudy, and show that Roma individuals carrying the GJB2 p.(Trp24*) and MANBA c.2158-2A>G variants have a more pronounced South Asian background, whereas the other hearing-impaired Roma display an ancestral background similar to Europeans. We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI.
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http://dx.doi.org/10.1038/s41431-019-0372-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777543PMC
June 2019

Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance.

Authors:
Khurram Liaqat Isabelle Schrauwen Syed Irfan Raza Kwanghyuk Lee Shabir Hussain Imen Chakchouk Abdul Nasir Anushree Acharya Izoduwa Abbe Muhammad Umair Muhammad Ansar Irfan Ullah Khadim Shah Michael J Bamshad Deborah A Nickerson Wasim Ahmad Suzanne M Leal

J Hum Genet 2019 Feb 30;64(2):153-160. Epub 2018 Nov 30.

Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Sinoatrial node dysfunction and deafness (SANDD) syndrome is rare and characterized by a low heart beat and severe-to-profound deafness. Additional features include fatigue, dizziness, and episodic syncope. The sinoatrial node (SAN) drives heart automaticity and continuously regulates heart rate. The CACNA1D gene encoding the Ca1.3 protein expressed in inner hair cells, atria and SAN, induces loss-of-function in channel activity and underlies SANDD. To date, only one variant c.1208_1209insGGG:p.(G403_V404insG) has been reported for SANDD syndrome. We studied five Pakistani families with SANDD and characterized a new missense variant p.(A376V) in CACNA1D in one family, and further characterized the founder variant p.(G403_V404insG) in four additional pedigrees. We show that affected individuals in the four families which segregate p.(G403_V404insG) share a 1.03 MB haplotype on 3p21.1 suggesting they share a common distant ancestor. In conclusion, we identified new and known variants in CACNA1D in five Pakistani families with SANDD. This study is of clinical importance as the CACNA1D founder variant is only observed in families from the Khyber Pakhtunkhwa (KPK) province, in Pakistan. Therefore, screening patients with congenital deafness for SAN dysfunction in this province could ensure adequate follow-up and prevent cardiac failure associated with SAN.
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http://dx.doi.org/10.1038/s10038-018-0542-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561484PMC
February 2019

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.

Authors:
Rabia Faridi Risa Tona Alessandra Brofferio Michael Hoa Rafal Olszewski Isabelle Schrauwen Muhammad Z K Assir Akhtar A Bandesha Asma A Khan Atteeq U Rehman Carmen Brewer Wasim Ahmed Suzanne M Leal Sheikh Riazuddin Steven E Boyden Thomas B Friedman

Hum Mutat 2019 02 12;40(2):162-176. Epub 2018 Dec 12.

Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.
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http://dx.doi.org/10.1002/humu.23689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328321PMC
February 2019

FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice.

Authors:
Isabelle Schrauwen Arnaud Pj Giese Abdul Aziz David Tino Lafont Imen Chakchouk Regie Lyn P Santos-Cortez Kwanghyuk Lee Anushree Acharya Falak Sher Khan Asmat Ullah Deborah A Nickerson Michael J Bamshad Ghazanfar Ali Saima Riazuddin Muhammad Ansar Wasim Ahmad Zubair M Ahmed Suzanne M Leal

J Bone Miner Res 2019 02 5;34(2):375-386. Epub 2018 Nov 5.

Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Polydactyly is a common congenital anomaly of the hand and foot. Postaxial polydactyly (PAP) is characterized by one or more posterior or postaxial digits. In a Pakistani family with autosomal recessive nonsyndromic postaxial polydactyly type A (PAPA), we performed genomewide genotyping, linkage analysis, and exome and Sanger sequencing. Exome sequencing revealed a homozygous nonsense variant (c.478C>T, p.[Arg160*]) in the FAM92A gene within the mapped region on 8q21.13-q24.12 that segregated with the PAPA phenotype. We found that FAM92A is expressed in the developing mouse limb and E11.5 limb bud including the progress zone and the apical ectodermal ridge, where it strongly localizes at the cilia level, suggesting an important role in limb patterning. The identified variant leads to a loss of the FAM92A/Chibby1 complex that is crucial for ciliogenesis and impairs the recruitment and the colocalization of FAM92A with Chibby1 at the base of the cilia. In addition, we show that Fam92a homozygous mice also exhibit an abnormal digit morphology, including metatarsal osteomas and polysyndactyly, in addition to distinct abnormalities on the deltoid tuberosity of their humeri. In conclusion, we present a new nonsyndromic PAPA ciliopathy due to a loss-of-function variant in FAM92A. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489482PMC
February 2019

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.

Authors:
Elodie M Richard Regie Lyn P Santos-Cortez Rabia Faridi Atteeq U Rehman Kwanghyuk Lee Mohsin Shahzad Anushree Acharya Asma A Khan Ayesha Imtiaz Imen Chakchouk Christina Takla Izoduwa Abbe Maria Rafeeq Khurram Liaqat Taimur Chaudhry Michael J Bamshad Deborah A Nickerson Isabelle Schrauwen Shaheen N Khan Robert J Morell Saba Zafar Muhammad Ansar Zubair M Ahmed Wasim Ahmad Sheikh Riazuddin Thomas B Friedman Suzanne M Leal Saima Riazuddin

Hum Mutat 2019 01 18;40(1):53-72. Epub 2018 Nov 18.

Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland.

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.
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http://dx.doi.org/10.1002/humu.23666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296877PMC
January 2019

Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis.

Authors:
Isabelle Schrauwen Hanne Valgaeren Laura Tomas-Roca Manou Sommen Umut Altunoglu Mieke Wesdorp Matthias Beyens Erik Fransen Abdul Nasir Geert Vandeweyer Anne Schepers Malika Rahmoun Ellen van Beusekom Matt J Huentelman Erwin Offeciers Ingeborg Dhooghe Alex Huber Paul Van de Heyning Diego Zanetti Els M R De Leenheer Christian Gilissen Alexander Hoischen Cor W Cremers Berit Verbist Arjan P M de Brouwer George W Padberg Ronald Pennings Hülya Kayserili Hannie Kremer Guy Van Camp Hans van Bokhoven

Genet Med 2019 05 5;21(5):1199-1208. Epub 2018 Oct 5.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis.

Methods: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls.

Results: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060).

Conclusion: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.
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http://dx.doi.org/10.1038/s41436-018-0300-5DOI Listing
May 2019

Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa.

Authors:
Zahid Latif Imen Chakchouk Isabelle Schrauwen Kwanghyuk Lee Regie Lyn P Santos-Cortez Izoduwa Abbe Anushree Acharya Afeefa Jarral Imran Ali Ehsan Ullah Muhammad Nasim Khan Ghazanfar Ali Tufail Hussain Tahir Michael J Bamshad Deborah A Nickerson Wasim Ahmad Muhammad Ansar Suzanne M Leal

Invest Ophthalmol Vis Sci 2018 09;59(11):4552-4557

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.

Purpose: Retinitis pigmentosa (RP) is a genetically heterogeneous trait with autosomal-recessive (ar) inheritance underlying 50% of genetic disease cases. Sixty-one arRP genes have been identified, and recently, DHX38 has been reported as a potential candidate gene for arRP with only a single family reported with a variant of unknown significance. We identified a missense variant in DHX38 that co-segregates with the arRP phenotype in two Pakistani families confirming the involvement of DHX38 in the etiology of early-onset RP.

Methods: Exome sequencing was performed using two DNA samples from affected members of Pakistani families (MA88 and MA157) with early onset arRP. Sanger sequencing of DNA samples from all family members confirmed the segregation of candidate variant within both families.

Results: A novel missense DHX38 variant c.971G>A; p.(Arg324Gln) was identified which segregates with the arRP phenotype and yielded a logarithm of the odds (LOD) score of 5.0 and 4.3 for families MA88 and MA157, respectively. This variant is predicted to be conserved and deleterious by several bioinformatics tools.

Conclusions: We identified a second deleterious DHX38 variant that segregates with arRP in two families, providing additional evidence that DHX38 is involved in RP etiology. DHX38 encodes for pre-mRNA splicing factor PRP16, which is important in catalyzing pre-mRNA splicing.
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http://dx.doi.org/10.1167/iovs.18-23849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133250PMC
September 2018

Novel missense and 3'-UTR splice site variants in LHFPL5 cause autosomal recessive nonsyndromic hearing impairment.

Authors:
Khurram Liaqat Ilene Chiu Kwanghyuk Lee Imen Chakchouk Paula B Andrade-Elizondo Regie Lyn P Santos-Cortez Shabir Hussain Shoaib Nawaz Muhammad Ansar Muhammad Nasim Khan Sulman Basit Isabelle Schrauwen Wasim Ahmad Suzanne M Leal

J Hum Genet 2018 Nov 3;63(11):1099-1107. Epub 2018 Sep 3.

Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

LHFPL5, the gene for DFNB67, underlies autosomal recessive nonsyndromic hearing impairment. We identified seven Pakistani families that mapped to 6p21.31, which includes the LHFPL5 gene. Sanger sequencing of LHFPL5 using DNA samples from hearing impaired and unaffected members of these seven families identified four variants. Among the identified variants, two were novel: one missense c.452 G > T (p.Gly151Val) and one splice site variant (c.*16 + 1 G > A) were each identified in two families. Two known variants: c.250delC (p.Leu84*) and c.380 A > G (p.Tyr127Cys) were also observed in two families and a single family, respectively. Nucleotides c.452G and c.*16 + 1G and amino-acid residue p.Gly151 are under strong evolutionary conservation. In silico bioinformatics analyses predicted these variants to be damaging. The splice site variant (c.*16 + 1 G > A) is predicted to affect pre-mRNA splicing and a loss of the 5' donor splice site in the 3'-untranslated region (3'-UTR). Further analysis supports the activation of a cryptic splice site approximately 357-bp downstream, leading to an extended 3'-UTR with additional regulatory motifs. In conclusion, we identified two novel variants in LHFPL5, including a unique 3'-UTR splice site variant that is predicted to impact pre-mRNA splicing and regulation through an extended 3'-UTR.
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http://dx.doi.org/10.1038/s10038-018-0502-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202120PMC
November 2018

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.

Authors:
Regie Lyn P Santos-Cortez Valeed Khan Falak Sher Khan Zaib-Un-Nisa Mughal Imen Chakchouk Kwanghyuk Lee Memoona Rasheed Rifat Hamza Anushree Acharya Ehsan Ullah Muhammad Arif Nadeem Saqib Izoduwa Abbe Ghazanfar Ali Muhammad Jawad Hassan Saadullah Khan Zahid Azeem Irfan Ullah Michael J Bamshad Deborah A Nickerson Isabelle Schrauwen Wasim Ahmad Muhammad Ansar Suzanne M Leal

Hum Genet 2018 Sep 22;137(9):735-752. Epub 2018 Aug 22.

Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA.

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.
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http://dx.doi.org/10.1007/s00439-018-1928-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201268PMC
September 2018