Publications by authors named "Regie Lyn P Santos-Cortez"

49 Publications

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

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 Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies.

Genes (Basel) 2021 04 13;12(4). Epub 2021 Apr 13.

Philippine National Ear Institute, University of the Philippines (UP) Manila-National Institutes of Health (NIH), Manila 1000, Philippines.

Hearing loss remains an important global health problem that is potentially addressed through early identification of a genetic etiology, which helps to predict outcomes of hearing rehabilitation such as cochlear implantation and also to mitigate the long-term effects of comorbidities. The identification of variants for hearing loss and detailed descriptions of clinical phenotypes in patients from various populations are needed to improve the utility of clinical genetic screening for hearing loss. Clinical and exome data from 15 children with hearing loss were reviewed. Standard tools for annotating variants were used and rare, putatively deleterious variants were selected from the exome data. In 15 children, 21 rare damaging variants in 17 genes were identified, including: 14 known hearing loss or neurodevelopmental genes, 11 of which had novel variants; and three candidate genes , and , two of which were identified in children with both hearing loss and enlarged vestibular aqueducts. Patients with variants within and had poorer outcomes after cochlear implantation. Our findings highlight the importance of identifying novel variants and genes in ethnic groups that are understudied for hearing loss.
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http://dx.doi.org/10.3390/genes12040566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069784PMC
April 2021

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

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

Novel Variants in Hearing Loss Genes and Associations With Audiometric Thresholds in a Multi-ethnic Cohort of US Patients With Cochlear Implants.

Otol Neurotol 2020 08;41(7):978-985

Department of Otolaryngology, School of Medicine, University of Colorado Anschutz Medical Campus.

Objectives: To investigate novel variants in hearing loss genes and clinical factors affecting audiometric outcomes of cochlear implant (CI) patients.

Background: Approximately 50% of hearing loss has a genetic etiology, with certain genetic variants more prevalent in specific ethnic groups. Different variants and some clinical variables including inner ear malformations result in different prognoses or clinical outcomes after CI.

Methods: Medical and genetic testing records of pediatric CI patients were reviewed for clinical variables. Minor allele frequencies of variants were obtained from Genome Aggregation Database (gnomAD) and variants were classified for pathogenicity. Standard statistical testing was done using Fisher's exact, Wilcoxon, and Spearman correlation tests.

Results: Eighteen CI patients with genetic test results had pathogenic variants, including six patients with syndromic hearing loss and six patients with known GJB2 variants. Novel pathogenic variants were noted in CHD7, ADGRV1, and ARID1B, with variants in the latter two genes identified in Hispanic patients. Overall, carriage of genetic variants was associated with better pre-CI audiometric thresholds at 2000 Hz (p = 0.048). On the other hand, post-CI thresholds were significantly worse in patients with inner ear malformations, particularly in patients with atretic cochlear nerve canals.

Conclusion: Four novel pathogenic variants were identified, which contributes to knowledge of allelic spectrum for hearing loss especially in Hispanic patients. In this cohort, carriage of pathogenic variants particularly of GJB2 variants was associated with better pre-CI audiometric thresholds, while patients with inner ear malformations had worse post-CI audiometric thresholds.
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http://dx.doi.org/10.1097/MAO.0000000000002671DOI Listing
August 2020

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

Front Genet 2019 17;10:1352. Epub 2020 Jan 17.

Department of Otolaryngology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genome-wide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes ( = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes and overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be used as reference for identification of genes or pathways that are relevant to upper and lower airways, whether common across sites, or unique to each disease.
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http://dx.doi.org/10.3389/fgene.2019.01352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979043PMC
January 2020

Panel 3: Genomics, precision medicine and targeted therapies.

Int J Pediatr Otorhinolaryngol 2020 Mar 24;130 Suppl 1:109835. Epub 2019 Dec 24.

Center for Genomic Sciences, Institute for Molecular Medicine and Infectious Disease, Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N. 15th St., Philadelphia, PA 19102, USA. Electronic address:

Objective: To review the most recent advances in human and bacterial genomics as applied to pathogenesis and clinical management of otitis media.

Data Sources: PubMed articles published since the last meeting in June 2015 up to June 2019.

Review Methods: A panel of experts in human and bacterial genomics of otitis media was formed. Each panel member reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019, discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members.

Conclusion: Trans-disciplinary approaches applying pan-omic technologies to identify human susceptibility to otitis media and to understand microbial population dynamics, patho-adaptation and virulence mechanisms are crucial to the development of novel, personalized therapeutics and prevention strategies for otitis media.

Implications For Practice: In the future otitis media prevention strategies may be augmented by mucosal immunization, combination vaccines targeting multiple pathogens, and modulation of the middle ear microbiome. Both treatment and vaccination may be tailored to an individual's otitis media phenotype as defined by molecular profiles obtained by using rapidly developing techniques in microbial and host genomics.
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http://dx.doi.org/10.1016/j.ijporl.2019.109835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155947PMC
March 2020

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

Genotype and Blood Type Are Associated with Otitis Media.

Genet Test Mol Biomarkers 2019 Nov;23(11):823-827

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

To determine if there is an association between variants or blood types and otitis media. DNA samples from 214 probands from Finnish families with recurrent acute (RAOM) and/or chronic otitis media with effusion (COME) were submitted for exome sequencing. Fisher exact tests were performed when (a) comparing frequencies of ABO genotypes in the Finnish probands with otitis media vs. counts in gnomAD Finnish, and (b) within the Finnish family cohort, comparing occurrence of RAOM vs. COME according to genotype/haplotype and predicted blood type. Female sex is protective against having both RAOM and COME. The wildtype genotype for the c.260insG (p.Val87_Thr88fs*) variant resulting in blood type O was protective against RAOM. On the other hand, type A was associated with increased risk for COME. These findings remained significant after adjustment for age and sex. Within the Finnish family cohort, the wildtype genotype for the c.260insG (p.Val87_Thr88fs*) variant and type O are protective against RAOM while type A increases risk for COME. This suggests that the association between the locus and otitis media is specific to blood type, otitis media type and cohort.
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http://dx.doi.org/10.1089/gtmb.2019.0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857544PMC
November 2019

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

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

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

Hum Mutat 2019 08 21;40(8):1156-1171. Epub 2019 May 21.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.
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http://dx.doi.org/10.1002/humu.23769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711784PMC
August 2019

Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly.

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

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Am J Hum Genet 2018 11 25;103(5):679-690. Epub 2018 Oct 25.

Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154, and p.Arg202-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217759PMC
November 2018

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

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.

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

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

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.

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.

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

The SLC26A4 c.706C>G (p.Leu236Val) Variant is a Frequent Cause of Hearing Impairment in Filipino Cochlear Implantees.

Otol Neurotol 2018 09;39(8):e726-e730

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

Hypothesis: Variants in SLC26A4 are an important cause of congenital hearing impairment in the Philippines.

Background: Cochlear implantation is a standard rehabilitation option for congenital hearing impairment worldwide, but places a huge cost burden in lower-income countries. The study of risk factors such as genetic variants that may help determine genetic etiology of hearing loss and also predict cochlear implant outcomes is therefore beneficial.

Methods: DNA samples from 29 GJB2-negative Filipino cochlear implantees were Sanger-sequenced for the coding exons of SLC26A4. Exome sequencing was performed to confirm results.

Results: Four cochlear implantees with bilaterally enlarged vestibular aqueducts (EVA) were homozygous for the pathogenic SLC26A4 c.706C>G (p.Leu236Val) variant, which has a minor allele frequency of 0.0015 in Filipino controls. In patients with the SLC26A4 variant there was no association between cochlear implant outcome and age at implantation or duration of implant. There was also no association between the occurrence of the SLC26A4 variant and postsurgical audiometric thresholds and parents' evaluation of aural/oral performance of children (PEACH) scores. On the other hand, the SLC26A4 variant increased presurgical median audiometric thresholds (p = 0.01), particularly at 500 to 2000 Hz.

Conclusion: The SLC26A4 c.706C>G (p.Leu236Val) variant is a frequent cause of congenital hearing impairment in Filipinos and is associated with bilateral EVA and increased presurgical audiometric thresholds, but does not adversely affect post-implant outcomes.
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http://dx.doi.org/10.1097/MAO.0000000000001893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097524PMC
September 2018

Genetic counseling in an indigenous Filipino community with a high prevalence of A2ML1-related otitis media.

J Community Genet 2019 Jan 15;10(1):143-151. Epub 2018 Jun 15.

Philippine National Ear Institute, UP Manila - NIH, Manila, Philippines.

In this report, we describe the knowledge and beliefs on causes and management of otitis media of an indigenous Filipino community with a high prevalence of otitis media that is associated with an A2ML1 variant. Community lectures and individual genetic counseling were provided as intervention. Knowledge, beliefs, and health care-seeking behavior pertaining to otitis media were assessed pre- and post-genetic counseling. Twenty-five heads of households were interviewed. Beliefs regarding etiology of ear discharge varied widely, with swimming in the sea as the most commonly cited cause of ear discharge. During the post-counseling session, poor personal hygiene, dirty environment, and familial inheritance were mentioned as risk factors for otitis media or ear discharge. Knowledge about the genotypes for the A2ML1 variant and otitis media diagnoses within the household influenced beliefs on the role of hygiene and genetic susceptibility to otitis media and attitudes towards health care-seeking behavior. Genetic counseling was associated with variable improvement in knowledge on otitis media and in their understanding of genetic susceptibility to otitis media due to the A2ML1 variant. Language barriers, literacy level, cultural factors, and the complex nature of genetic information made genetic counseling in the particular population a challenge. Insights drawn from this experience recommend follow-up visits in the community.
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http://dx.doi.org/10.1007/s12687-018-0368-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325045PMC
January 2019

A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family.

Eur J Dermatol 2018 Apr;28(2):209-216

Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University (QAU), Islamabad, 45320, Pakistan.

Autosomal recessive ichthyosis with hypotrichosis (ARIH; MIM 602400) syndrome is characterized by diffused congenital ichthyosis and generalized non-scarring hypotrichosis. The underlying genetic cause of ARIH syndrome has been associated with sequence variants of the gene ST14, encoding type II transmembrane serine protease matriptase, which maps to chromosome 11q24.3. The current report aimed to investigate the clinical features and genetic cause of ARIH syndrome in a large consanguineous family of Pakistani origin. The technique of homozygosity mapping with highly polymorphic microsatellite markers was employed to establish linkage within the family. Sanger sequencing of exons and intron-exon boundaries of ST14 was performed to identify the potential pathogenic sequence variants, followed by structural analysis of the mutated protein. Linkage was established to chromosome 11q24.3, comprising the gene ST14. Sequence analysis led to the identification of a novel homozygous missense variant (c.1315G>A, p.Gly439Ser) in the ST14 gene that co-segregated with the disease phenotype in all affected members. Homology modelling and molecular docking analysis of ST14 with wild-type TMEFF1 protein was performed which revealed that glycine at position 439 is crucial for maintaining normal structural confirmation and interaction with the EGF domain of TMEFF1 protein. Taken together, the data strongly advocate this ST14 variant as the underlying genetic cause of ARIH syndrome in this first reported affected family from Pakistan. Moreover, the present study adds to the spectrum of mutations in the ST14 gene, implicating them in the pathogenesis of ARIH syndrome.
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http://dx.doi.org/10.1684/ejd.2017.3210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240033PMC
April 2018

Identification of ASAH1 as a susceptibility gene for familial keloids.

Eur J Hum Genet 2017 10 26;25(10):1155-1161. Epub 2017 Jul 26.

Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT, USA.

Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.
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http://dx.doi.org/10.1038/ejhg.2017.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602022PMC
October 2017

Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population.

Otolaryngol Head Neck Surg 2016 11 2;155(5):856-862. Epub 2016 Aug 2.

Philippine National Ear Institute, University of the Philippines Manila-National Institutes of Health, Manila, Philippines.

Objective: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population.

Study Design: Cross-sectional study.

Setting: Indigenous Filipino community.

Subjects And Methods: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster.

Results: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1-variant carriers.

Conclusion: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.
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http://dx.doi.org/10.1177/0194599816661703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093071PMC
November 2016

Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene.

Infect Dis Poverty 2016 Nov 1;5(1):97. Epub 2016 Nov 1.

Philippine National Ear Institute, University of the Philippines Manila - National Institutes of Health (UPM-NIH), Manila, 1000, Philippines.

Background: Previously rare A2ML1 variants were identified to confer otitis media susceptibility in an indigenous Filipino community and in otitis-prone US children. The goal of this study is to describe differences in the middle ear microbiome between carriers and non-carriers of an A2ML1 duplication variant that increases risk for chronic otitis media among indigenous Filipinos with poor health care access.

Methods: Ear swabs were obtained from 16 indigenous Filipino individuals with chronic otitis media, of whom 11 carry the A2ML1 duplication variant. Ear swabs were submitted for 16S rRNA gene sequencing.

Results: Genotype-based differences in microbial richness, structure, and composition were identified, but were not statistically significant. Taxonomic analysis revealed that the relative abundance of the phyla Fusobacteria and Bacteroidetes, and genus Fusobacterium were nominally increased in carriers compared to non-carriers, but were non-significant after correction for multiple testing. We also detected rare bacteria including Oligella that was reported only once in the middle ear.

Conclusions: These findings suggest that A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome. Knowledge of middle ear microbial profiles according to genetic background can be potentially useful for therapeutic and prophylactic interventions for otitis media and can guide public health interventions towards decreasing otitis media prevalence within the indigenous Filipino community.
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http://dx.doi.org/10.1186/s40249-016-0189-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088646PMC
November 2016

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

J Am Heart Assoc 2016 07 14;5(7). Epub 2016 Jul 14.

Surgery Department, University of Otago, Dunedin, New Zealand.

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs.

Methods And Results: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)).

Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
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http://dx.doi.org/10.1161/JAHA.115.002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015357PMC
July 2016

Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.

Hum Mutat 2016 10 21;37(10):991-1003. Epub 2016 Aug 21.

Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, 20892.

Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal-recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.
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http://dx.doi.org/10.1002/humu.23042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021573PMC
October 2016

Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP.

BMC Med Genet 2016 Feb 16;17:13. Epub 2016 Feb 16.

Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.

Background: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity.

Methods: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression.

Results: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old.

Conclusion: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype.
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http://dx.doi.org/10.1186/s12881-016-0275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754937PMC
February 2016

LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

Circ Res 2016 Mar 12;118(6):928-34. Epub 2016 Jan 12.

From the Departments of Internal Medicine (D.G., E.S.R., L.G., X.D., Z.R., B.C., E.M.H., D.M.M.) and Cardiothoracic and Vascular Surgery (A.E., H.J.S.), University of Texas Health Science Center, Houston; Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L.); Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat, Paris, France (P.A., G.J., C.B.); Centre National de Référence pour le syndrome de Marfan et apparentés, Département de Génétique Moléculaire, AP-HP, Hôpital Bichat, Paris, France (P.A., C.B.); Department of Pediatrics, MetroHealth Medical Center, Cleveland, OH (R.M.); Department of Medicine, Stanford University Medical Center, CA (D.L.); and Department of Genome Sciences, University of Washington, Seattle (M.J.B., J.S., D.A.N.).

Rationale: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families.

Objectives: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections.

Methods And Results: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections.

Conclusions: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.307130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839295PMC
March 2016
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