Publications by authors named "Suzanne M Leal"

206 Publications

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

J Hum Genet 2021 Sep 16. Epub 2021 Sep 16.

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

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http://dx.doi.org/10.1038/s10038-021-00951-9DOI Listing
September 2021

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.

Genet Med 2021 Aug 3. Epub 2021 Aug 3.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.

Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.

Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.

Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
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http://dx.doi.org/10.1038/s41436-021-01246-2DOI Listing
August 2021

The role of CDHR3 in susceptibility to otitis media.

J Mol Med (Berl) 2021 Jul 28. Epub 2021 Jul 28.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus (CU-AMC), 12700 E. 19th Ave, Aurora, CO, 80045, USA.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.
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http://dx.doi.org/10.1007/s00109-021-02118-7DOI Listing
July 2021

Delineating the genotypic and phenotypic spectrum of -related neurodevelopmental disorders.

J Med Genet 2021 Jul 28. Epub 2021 Jul 28.

GeneDx, Gaithersburg, Maryland, USA.

Background: Variants in have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.

Methods: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a related neurodevelopmental disorder.

Results: We identified 13 novel missense variants in in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.

Conclusion: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of disorders, aiding future molecular and clinical diagnosis and management.
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http://dx.doi.org/10.1136/jmedgenet-2021-107871DOI Listing
July 2021

Identification of autosomal recessive nonsyndromic hearing impairment genes through the study of consanguineous and non-consanguineous families: past, present, and future.

Hum Genet 2021 Jul 22. Epub 2021 Jul 22.

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

Hearing impairment (HI) is one of the most common sensory disabilities with exceptionally high genetic heterogeneity. Of genetic HI cases, 30% are syndromic and 70% are nonsyndromic. For nonsyndromic (NS) HI, 77% of the cases are due to autosomal recessive (AR) inheritance. ARNSHI is usually congenital/prelingual, severe-to-profound, affects all frequencies and is not progressive. Thus far, 73 ARNSHI genes have been identified. Populations with high rates of consanguinity have been crucial in the identification of ARNSHI genes, and 92% (67/73) of these genes were identified in consanguineous families. Recent changes in genomic technologies and analyses have allowed a shift towards ARNSHI gene discovery in outbred populations. The latter is crucial towards understanding the genetic architecture of ARNSHI in diverse and understudied populations. We present an overview of the 73 ARNSHI genes, the methods used to identify them, including next-generation sequencing which revolutionized the field, and new technologies that show great promise in advancing ARNSHI discoveries.
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http://dx.doi.org/10.1007/s00439-021-02309-9DOI Listing
July 2021

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Am J Hum Genet 2021 09 14;108(9):1578-1589. Epub 2021 Jul 14.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456156PMC
September 2021

Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment.

J Hum Genet 2021 Jul 5. Epub 2021 Jul 5.

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

Congenital hearing impairment (HI) is genetically heterogeneous making its genetic diagnosis challenging. Investigation of novel HI genes and variants will enhance our understanding of the molecular mechanisms and to aid genetic diagnosis. We performed exome sequencing and analysis using DNA samples from affected members of two large families from Ghana and Pakistan, segregating autosomal-dominant (AD) non-syndromic HI (NSHI). Using in silico approaches, we modeled and evaluated the effect of the likely pathogenic variants on protein structure and function. We identified two likely pathogenic variants in SLC12A2, c.2935G>A:p.(E979K) and c.2939A>T:p.(E980V), which segregate with NSHI in a Ghanaian and Pakistani family, respectively. SLC12A2 encodes an ion transporter crucial in the homeostasis of the inner ear endolymph and has recently been reported to be implicated in syndromic and non-syndromic HI. Both variants were mapped to alternatively spliced exon 21 of the SLC12A2 gene. Exon 21 encodes for 17 residues in the cytoplasmatic tail of SLC12A2, is highly conserved between species, and preferentially expressed in cochlear tissues. A review of previous studies and our current data showed that out of ten families with either AD non-syndromic or syndromic HI, eight (80%) had variants within the 17 amino acid residue region of exon 21 (48 bp), suggesting that this alternate domain is critical to the transporter activity in the inner ear. The genotypic spectrum of SLC12A2 was expanded and the involvement of SLC12A2 in ADNSHI was confirmed. These results also demonstrate the role that SLC12A2 plays in ADNSHI in diverse populations including sub-Saharan Africans.
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http://dx.doi.org/10.1038/s10038-021-00954-6DOI Listing
July 2021

ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment.

Eur J Hum Genet 2021 Jun 16. Epub 2021 Jun 16.

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

Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.
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http://dx.doi.org/10.1038/s41431-021-00913-xDOI Listing
June 2021

Identification of microduplications at Xp21.2 and Xq13.1 in neurodevelopmental disorders.

Mol Genet Genomic Med 2021 May 12:e1703. Epub 2021 May 12.

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

Background: Microduplications are a rare cause of disease in X-linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation.

Methods: We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder.

Results: Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8-kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223- and 204-kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re-arrangement.

Conclusion: In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X-chromosome can be helpful in undiagnosed cases of neurodevelopmental disease.
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http://dx.doi.org/10.1002/mgg3.1703DOI Listing
May 2021

Wolfram-like syndrome with bicuspid aortic valve due to a homozygous missense variant in CDK13.

J Hum Genet 2021 Oct 21;66(10):1009-1018. Epub 2021 Apr 21.

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

Background: Wolfram syndrome (WFS) is characterized by deafness, diabetes mellitus, and diabetes insipidus along with optic atrophy. WFS has an autosomal recessive mode of inheritance and is due to variants in WFS1 and CISD2.

Methods: We evaluated the underlying molecular etiology of three affected members of a consanguineous family with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities via exome sequencing approach. We correlated clinical and imaging data with the genetic findings and their associated phenotypes.

Results: We identified a homozygous missense variant p.(Asn1097Lys) in CDK13, a gene previously associated with autosomal dominant congenital heart defects, dysmorphic facial features, clinodactyly, gastrointestinal tract abnormalities, intellectual developmental disorder, and seizures with variable phenotypic features.

Conclusion: We report a homozygous variant in CDK13 and suggest that this gene causes an autosomal recessive disorder with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities.
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http://dx.doi.org/10.1038/s10038-021-00922-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472924PMC
October 2021

A novel variant in gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family.

Exp Biol Med (Maywood) 2021 Jul 9;246(13):1524-1532. Epub 2021 Mar 9.

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

Approximately half of congenital hearing impairment cases are inherited, with non-syndromic hearing impairment (NSHI) being the most frequent clinical entity of genetic hearing impairment cases. A family from Cameroon with NSHI was investigated by performing exome sequencing using DNA samples obtained from three family members, followed by direct Sanger sequencing in additional family members and controls participants. We identified an autosomal dominantly inherited novel missense variant [NM_001174116.2:c.918G>T; p.(Q306H)] in gene (MIM:612186) that co-segregates with mild to profound non-syndromic sensorineural hearing impairment . The p.(Q306H) variant which substitutes a highly conserved glutamine residue is predicted deleterious by various bioinformatics tools and is absent from several genome databases. This variant was also neither found in 121 apparently healthy controls without a family history of hearing impairment , nor 112 sporadic NSHI cases from Cameroon. There is one previous report of a large Han Chinese NSHI family that segregates a missense variant in . The present study provides additional evidence that is involved in hearing impairment etiology, and we suggest should be considered in diagnostic hearing impairment panels.
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http://dx.doi.org/10.1177/1535370221999746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283254PMC
July 2021

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.

Hum Genet 2021 Jul 12;140(7):1011-1029. Epub 2021 Mar 12.

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, USA.

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.
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http://dx.doi.org/10.1007/s00439-021-02268-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197721PMC
July 2021

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

Genes (Basel) 2020 10 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.

Genes (Basel) 2020 10 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.

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.

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

Multi-omic studies on missense PLG variants in families with otitis media.

Sci Rep 2020 09 14;10(1):15035. Epub 2020 Sep 14.

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

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.
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http://dx.doi.org/10.1038/s41598-020-70498-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490366PMC
September 2020

A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer's disease.

Eur J Hum Genet 2020 12 1;28(12):1734-1742. Epub 2020 Aug 1.

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer's disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p < 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.
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http://dx.doi.org/10.1038/s41431-020-0703-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785016PMC
December 2020

Otitis media susceptibility and shifts in the head and neck microbiome due to variants.

J Med Genet 2021 07 24;58(7):442-452. Epub 2020 Jul 24.

Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

Background: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.

Methods: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues.

Results: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare variants, a common variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within (LOD=4.09). Carriage of the missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel variants were identified in 12 families and individuals with OM. A role for in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased expression in human cholesteatoma.

Conclusion: variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.
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http://dx.doi.org/10.1136/jmedgenet-2020-106844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218788PMC
July 2021

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

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

A non-coding RNASEH1 gene variant associates with type 1 diabetes and interacts with HLA tagSNPs in families from Colombia.

Pediatr Diabetes 2020 11 23;21(7):1183-1192. Epub 2020 Jul 23.

Grupo Mapeo Genetico, Departamento de Pediatria, Universidad de Antioquia, Medellín, Colombia.

Objectives: RNASEH1 gene has recently been associated with type 1 diabetes (T1D) in Colombia. The purpose of this study was to fine mapping the putative functional variant in RNASEH1 and testing its interaction with HLA tagSNPs.

Methods: Two-hundred nuclear families with T1D were included in this study. Probands were tested for GAD65 and IA-2 autoantibodies. Genotyping was performed using 20 coding tagSNPs uncovered through Sanger sequencing (N = 96), in addition to 23 tagSNPs chosen from 1000genomes to cover the extent of the gene region. Also, 45 tagSNPs for classic HLA alleles associated with T1D were also genotyped. The transmission disequilibrium test (TDT) was used to test for association and a multiple testing correction was made using permutation. Interaction between RNASEH1 variants and HLA was evaluated by means of the M-TDT test.

Results: We identified 20 variants (15 were novel) in the 96 patients sequenced. None of these variants were in linkage disequilibrium. In total, 43 RNASEH1 variants were genotyped in the 200 families. Association between T1D and rs7607888 was identified (P = .002). Haplotype analysis involving rs7607888 variant revealed even stronger association with T1D (most significative P = .0003). HLA tagSNPs displayed stronger associations (OR = 6.39, 95% CI = 4.33-9.44, P-value = 9.74E-28). Finally, we found several statistically significant interactions of HLA variants with rs7607888 (P-value ranged from 8.77E-04 to 5.33E-12).

Conclusion: Our results verify the association of rs7607888 in RNASEH1 gene with T1D. It is also shown in the interaction between RNASEH1 and HLA for conveying risk to T1D in Northwest Colombia. Work is underway aiming to identify the actual classic HLA alleles associated with the tagSNPs tested here.
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http://dx.doi.org/10.1111/pedi.13057DOI Listing
November 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.

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

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

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240029PMC
July 2021

Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.

Am J Hum Genet 2020 02 9;106(2):234-245. Epub 2020 Jan 9.

Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010978PMC
February 2020

Type 1 diabetes loci display a variety of native American and African ancestries in diseased individuals from Northwest Colombia.

World J Diabetes 2019 Nov;10(11):534-545

Grupo Mapeo Genetico, Departamento de Pediatría, Facultad de Medicina, Universidad de Antioquia, Medellín 050010470, Colombia.

Background: Type 1 diabetes (T1D) is a complex disease with a higher incidence in Europeans than other populations. The Colombians Living in Medellin (CLM) is admixed with ancestry contributions from Europeans, Native Americans (NAT) and Africans (AFR).

Aim: Our aim was to analyze the genetic admixture component at candidate T1D loci in Colombian individuals with the disease.

Methods: Seventy-four ancestry informative markers (AIMs), which tagged 41 T1D candidate loci/genes, were tested by studying a cohort of 200 Northwest Colombia diseased individuals. T1D status was classified by testing for glutamic acid decarboxylase (GAD-65 kDa) and protein tyrosine-like antigen-2 auto-antibodies in serum samples. Candidate loci/genes included , , , , , , , , , , and , amongst others. The 1,000 genome database was used to analyze data from 94 individuals corresponding to the reference CLM. As the data did not comply with a normal distribution, medians were compared between groups using the Mann-Whitney -test.

Results: Both T1D patients and individuals from CLM displayed mainly European ancestry (61.58 62.06) followed by Native American (27.34 27.46) and to a lesser extent the AFR ancestry (10.28 10.65) components. However, compared to CLM, ancestry of T1D patients displayed a decrease of NAT ancestry at gene (24.30 37.10) and an increase at genes (32.07 14.99) and (52.18 39.18). Also, for gene (36.67 0.003), we observed a non-AFR contribution (attributed to NAT). Autoimmune patients (positive for any of two auto-antibodies) displayed lower NAT ancestry than idiopathic patients at the region (20.36 31.88). Also, late onset patients presented with greater AFR ancestry than early onset patients at gene (19.96 6.17). An association analysis showed that, even after adjusting for admixture, an association exists for at least seven such AIMs, with the strongest findings on chromosomes 5 and 10 (gene , = 5.56 × 10 and gene , = 8.70 × 10, respectively).

Conclusion: Although Colombian T1D patients have globally presented with higher European admixture, specific T1D loci have displayed varying levels of Native American and AFR ancestries in diseased individuals.
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http://dx.doi.org/10.4239/wjd.v10.i11.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885725PMC
November 2019

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

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216908PMC
January 2020

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

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 Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.

Am J Hum Genet 2019 10;105(4):822-835

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Taub Institute on Alzheimer Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY 10027, USA; Center for Statistical Genetics, Columbia University, New York, NY 10027, USA. Electronic address:

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817540PMC
October 2019

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

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
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