@article {512, title = {Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa.}, journal = {Invest Ophthalmol Vis Sci}, volume = {59}, year = {2018}, month = {2018 09 04}, pages = {4552-4557}, abstract = {

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.

}, keywords = {Adolescent, Adult, Cataract, Computational Biology, DEAD-box RNA Helicases, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, Humans, Male, Mutation, Missense, Nucleotide Mapping, Ophthalmoscopy, Pedigree, Retinitis Pigmentosa, RNA Splicing Factors, Sequence Analysis, DNA, Whole Exome Sequencing, Young Adult}, issn = {1552-5783}, doi = {10.1167/iovs.18-23849}, author = {Latif, Zahid and Chakchouk, Imen and Schrauwen, Isabelle and Lee, Kwanghyuk and Santos-Cortez, Regie Lyn P and Abbe, Izoduwa and Acharya, Anushree and Jarral, Afeefa and Ali, Imran and Ullah, Ehsan and Khan, Muhammad Nasim and Ali, Ghazanfar and Tahir, Tufail Hussain and Bamshad, Michael J and Nickerson, Deborah A and Ahmad, Wasim and Ansar, Muhammad and Leal, Suzanne M} } @article {83, title = {Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP.}, journal = {BMC Med Genet}, volume = {17}, year = {2016}, month = {2016 Feb 16}, pages = {13}, abstract = {

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.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Alleles, Asian Continental Ancestry Group, Child, Cloning, Molecular, Exome, Female, Genetic Linkage, Haplotypes, HEK293 Cells, Homozygote, Humans, Introns, Male, Mitral Valve Insufficiency, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA Splicing, Sequence Analysis, DNA, Trichothiodystrophy Syndromes, Young Adult}, issn = {1471-2350}, doi = {10.1186/s12881-016-0275-5}, author = {Shah, Khadim and Ali, Raja Hussain and Ansar, Muhammad and Lee, Kwanghyuk and Chishti, Muhammad Salman and Abbe, Izoduwa and Li, Biao and Smith, Joshua D and Nickerson, Deborah A and Shendure, Jay and Coucke, Paul J and Steyaert, Wouter and Bamshad, Michael J and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Ahmad, Wasim} } @article {150, title = {A homozygous missense variant in type I keratin KRT25 causes autosomal recessive woolly hair.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Oct}, pages = {676-80}, abstract = {

BACKGROUND: Woolly hair (WH) is a hair abnormality that is primarily characterised by tightly curled hair with abnormal growth.

METHODS: In two unrelated consanguineous Pakistani families with non-syndromic autosomal recessive (AR) WH, homozygosity mapping and linkage analysis identified a locus within 17q21.1-q22, which contains the type I keratin gene cluster. A DNA sample from an affected individual from each family underwent exome sequencing.

RESULTS: A homozygous missense variant c.950T>C (p.(Leu317Pro)) within KRT25 segregated with ARWH in both families, and has a combined maximum two-point LOD score of 7.9 at ϴ=0. The KRT25 variant is predicted to result in disruption of the second α-helical rod domain and the entire protein structure, thus possibly interfering with heterodimerisation of K25 with type II keratins within the inner root sheath (IRS) of the hair follicle and the medulla of the hair shaft.

CONCLUSIONS: Our findings implicate a novel gene involved in human hair abnormality, and are consistent with the curled, fragile hair found in mice with Krt25 mutations, and further support the role of IRS-specific type I keratins in hair follicle development and maintenance of hair texture.

}, keywords = {Child, Child, Preschool, Consanguinity, Hair, Hair Diseases, Humans, Keratins, Type I, Male, Mutation, Missense, Pakistan, Pedigree, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103255}, author = {Ansar, Muhammad and Raza, Syed Irfan and Lee, Kwanghyuk and Shahi, Shamim and Acharya, Anushree and Dai, Hang and Smith, Joshua D and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Santos-Cortez, Regie Lyn P and Ahmad, Wasim and Leal, Suzanne M} } @article {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {274, title = {Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {144-52}, abstract = {

Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.

}, keywords = {Alleles, Amino Acid Sequence, Carrier Proteins, Chromosomes, Human, Pair 16, Consanguinity, Deafness, Epilepsy, Exome, Exons, Female, Genes, Recessive, Genetic Loci, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Male, Molecular Sequence Data, Mutation, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA, Messenger, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.12.004}, author = {Rehman, Atteeq U and Santos-Cortez, Regie Lyn P and Morell, Robert J and Drummond, Meghan C and Ito, Taku and Lee, Kwanghyuk and Khan, Asma A and Basra, Muhammad Asim R and Wasif, Naveed and Ayub, Muhammad and Ali, Rana A and Raza, Syed I and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael and Riazuddin, Saima and Billington, Neil and Khan, Shaheen N and Friedman, Penelope L and Griffith, Andrew J and Ahmad, Wasim and Riazuddin, Sheikh and Leal, Suzanne M and Friedman, Thomas B} } @article {279, title = {Rare-variant extensions of the transmission disequilibrium test: application to autism exome sequence data.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {33-46}, abstract = {

Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.

}, keywords = {Alleles, Autistic Disorder, Computer Simulation, Exome, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Linkage Disequilibrium, Models, Genetic, Phenotype, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.021}, author = {He, Zongxiao and O{\textquoteright}Roak, Brian J and Smith, Joshua D and Wang, Gao and Hooker, Stanley and Santos-Cortez, Regie Lyn P and Li, Biao and Kan, Mengyuan and Krumm, Nik and Nickerson, Deborah A and Shendure, Jay and Eichler, Evan E and Leal, Suzanne M} }