@article {652, title = {Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Jun}, pages = {593-600}, abstract = {

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.

}, keywords = {Animals, Consanguinity, Family Health, Female, Fingers, Genes, Recessive, Genetic Predisposition to Disease, Genotype, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Inbred C57BL, Mutation, Pedigree, Phenotype, Polydactyly, Toes, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-02000-0}, author = {Ullah, Irfan and Kakar, Naseebullah and Schrauwen, Isabelle and Hussain, Shabir and Chakchouk, Imen and Liaqat, Khurram and Acharya, Anushree and Wasif, Naveed and Santos-Cortez, Regie Lyn P and Khan, Saadullah and Aziz, Abdul and Lee, Kwanghyuk and Couthouis, Julien and Horn, Denise and Kragesteen, Bj{\o}rt K and Spielmann, Malte and Thiele, Holger and Nickerson, Deborah A and Bamshad, Michael J and Gitler, Aaron D and Ahmad, Jamil and Ansar, Muhammad and Borck, Guntram and Ahmad, Wasim and Leal, Suzanne M} } @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 {498, title = {Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {735-752}, abstract = {

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.

}, keywords = {Adult, Consanguinity, Family, Female, Genes, Recessive, Genetic Markers, Humans, Intellectual Disability, Male, Middle Aged, Mutation, Neurodevelopmental Disorders, Pedigree}, issn = {1432-1203}, doi = {10.1007/s00439-018-1928-6}, author = {Santos-Cortez, Regie Lyn P and Khan, Valeed and Khan, Falak Sher and Mughal, Zaib-Un-Nisa and Chakchouk, Imen and Lee, Kwanghyuk and Rasheed, Memoona and Hamza, Rifat and Acharya, Anushree and Ullah, Ehsan and Saqib, Muhammad Arif Nadeem and Abbe, Izoduwa and Ali, Ghazanfar and Hassan, Muhammad Jawad and Khan, Saadullah and Azeem, Zahid and Ullah, Irfan and Bamshad, Michael J and Nickerson, Deborah A and Schrauwen, Isabelle and Ahmad, Wasim and Ansar, Muhammad and Leal, Suzanne M} } @article {89, title = {Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {331-8}, abstract = {

The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among \~{}120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were~observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2.

}, keywords = {Amino Acid Sequence, Asian Continental Ancestry Group, Chromosomes, Human, Pair 19, Exome, Genes, Recessive, Hearing Loss, Humans, Lod Score, Logistic Models, Lysophospholipids, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Receptors, Lysosphingolipid, Sphingosine}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.004}, author = {Santos-Cortez, Regie Lyn P and Faridi, Rabia and Rehman, Atteeq U and Lee, Kwanghyuk and Ansar, Muhammad and Wang, Xin and Morell, Robert J and Isaacson, Rivka and Belyantseva, Inna A and Dai, Hang and Acharya, Anushree and Qaiser, Tanveer A and Muhammad, Dost and Ali, Rana Amjad and Shams, Sulaiman and Hassan, Muhammad Jawad and Shahzad, Shaheen and Raza, Syed Irfan and Bashir, Zil-E-Huma and Smith, Joshua D and Nickerson, Deborah A and Bamshad, Michael J and Riazuddin, Sheikh and Ahmad, Wasim and Friedman, Thomas B and Leal, Suzanne M} } @article {204, title = {Challenges and solutions for gene identification in the presence of familial locus heterogeneity.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Sep}, pages = {1207-15}, abstract = {

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25\% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3\% (95\% confidence interval: 11.9\%, 19.9\%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

}, keywords = {Asian Continental Ancestry Group, Calcium-Binding Proteins, Chromosome Mapping, Connexin 26, Connexins, Consanguinity, European Continental Ancestry Group, Female, Genes, Recessive, Genetic Heterogeneity, Genetic Linkage, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genotype, Hearing Loss, Hepatocyte Growth Factor, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Membrane Transport Proteins, Mutation, Pedigree, Phenotype, Sulfate Transporters}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.266}, author = {Rehman, Atteeq U and Santos-Cortez, Regie Lyn P and Drummond, Meghan C and Shahzad, Mohsin and Lee, Kwanghyuk and Morell, Robert J and Ansar, Muhammad and Jan, Abid and Wang, Xin and Aziz, Abdul and Riazuddin, Saima and Smith, Joshua D and Wang, Gao T and Ahmed, Zubair M and Gul, Khitab and Shearer, A Eliot and Smith, Richard J H and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hinnant, John and Khan, Shaheen N and Fisher, Rachel A and Ahmad, Wasim and Friderici, Karen H and Riazuddin, Sheikh and Friedman, Thomas B and Wilch, Ellen S 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} }