@article {1004, title = {Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.}, journal = {Hum Genet}, year = {2021}, month = {2021 Mar 12}, abstract = {

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.

}, issn = {1432-1203}, doi = {10.1007/s00439-021-02268-1}, author = {J{\"a}rvel{\"a}, Irma and M{\"a}{\"a}tt{\"a}, Tuomo and Acharya, Anushree and Lepp{\"a}l{\"a}, Juha and Jhangiani, Shalini N and Arvio, Maria and Siren, Auli and Kankuri-Tammilehto, Minna and Kokkonen, Hannaleena and Palom{\"a}ki, Maarit and Varilo, Teppo and Fang, Mary and Hadley, Trevor D and Jolly, Angad and Linnankivi, Tarja and Paetau, Ritva and Saarela, Anni and K{\"a}lvi{\"a}inen, Reetta and Olme, Jan and Nouel-Saied, Liz M and Cornejo-Sanchez, Diana M and Llaci, Lorida and Lupski, James R and Posey, Jennifer E and Leal, Suzanne M and Schrauwen, Isabelle} } @article {699, title = {A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 08}, pages = {1156-1171}, abstract = {

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.

}, issn = {1098-1004}, doi = {10.1002/humu.23769}, author = {Larson, Eric D and Magno, Jose Pedrito M and Steritz, Matthew J and Llanes, Erasmo Gonzalo D V and Cardwell, Jonathan and Pedro, Melquiadesa and Roberts, Tori Bootpetch and Einarsdottir, Elisabet and Rosanes, Rose Anne Q and Greenlee, Christopher and Santos, Rachel Ann P and Yousaf, Ayesha and Streubel, Sven-Olrik and Santos, Aileen Trinidad R and Ruiz, Amanda G and Lagrana-Villagracia, Sheryl Mae and Ray, Dylan and Yarza, Talitha Karisse L and Scholes, Melissa A and Anderson, Catherine B and Acharya, Anushree and Gubbels, Samuel P and Bamshad, Michael J and Cass, Stephen P and Lee, Nanette R and Shaikh, Rehan S and Nickerson, Deborah A and Mohlke, Karen L and Prager, Jeremy D and Cruz, Teresa Luisa G and Yoon, Patricia J and Abes, Generoso T and Schwartz, David A and Chan, Abner L and Wine, Todd M and Cutiongco-de la Paz, Eva Maria and Friedman, Norman and Kechris, Katerina and Kere, Juha and Leal, Suzanne M and Yang, Ivana V and Patel, Janak A and Tantoco, Ma Leah C and Riazuddin, Saima and Chan, Kenny H and Mattila, Petri S and Reyes-Quintos, Maria Rina T and Ahmed, Zubair M and Jenkins, Herman A and Chonmaitree, Tasnee and Hafr{\'e}n, Lena and Chiong, Charlotte M and Santos-Cortez, Regie Lyn P} } @article {505, title = {FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice.}, journal = {J Bone Miner Res}, volume = {34}, year = {2019}, month = {2019 Feb}, pages = {375-386}, abstract = {

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. {\textcopyright} 2018 American Society for Bone and Mineral Research.

}, issn = {1523-4681}, doi = {10.1002/jbmr.3594}, author = {Schrauwen, Isabelle and Giese, Arnaud Pj and Aziz, Abdul and Lafont, David Tino and Chakchouk, Imen and Santos-Cortez, Regie Lyn P and Lee, Kwanghyuk and Acharya, Anushree and Khan, Falak Sher and Ullah, Asmat and Nickerson, Deborah A and Bamshad, Michael J and Ali, Ghazanfar and Riazuddin, Saima and Ansar, Muhammad and Ahmad, Wasim and Ahmed, Zubair M and Leal, Suzanne M} } @article {549, title = {Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 Jan}, pages = {53-72}, abstract = {

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.

}, issn = {1098-1004}, doi = {10.1002/humu.23666}, author = {Richard, Elodie M and Santos-Cortez, Regie Lyn P and Faridi, Rabia and Rehman, Atteeq U and Lee, Kwanghyuk and Shahzad, Mohsin and Acharya, Anushree and Khan, Asma A and Imtiaz, Ayesha and Chakchouk, Imen and Takla, Christina and Abbe, Izoduwa and Rafeeq, Maria and Liaqat, Khurram and Chaudhry, Taimur and Bamshad, Michael J and Nickerson, Deborah A and Schrauwen, Isabelle and Khan, Shaheen N and Morell, Robert J and Zafar, Saba and Ansar, Muhammad and Ahmed, Zubair M and Ahmad, Wasim and Riazuddin, Sheikh and Friedman, Thomas B and Leal, Suzanne M and Riazuddin, Saima} } @article {730, title = {Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Jun}, pages = {869-878}, abstract = {

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

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0372-y}, author = {Schrauwen, Isabelle and Melegh, B{\'e}la I and Chakchouk, Imen and Acharya, Anushree and Nasir, Abdul and Poston, Alexis and Cornejo-Sanchez, Diana M and Szabo, Zsolt and Karosi, Tam{\'a}s and Bene, Judit and Melegh, B{\'e}la and Leal, Suzanne M} } @article {660, title = {Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance.}, journal = {J Hum Genet}, volume = {64}, year = {2019}, month = {2019 Feb}, pages = {153-160}, abstract = {

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

}, keywords = {Adolescent, Calcium Channels, L-Type, Deafness, Female, Heart Diseases, Humans, Male, Mutation, Pakistan, Pedigree, Prognosis, Sinoatrial Node}, issn = {1435-232X}, doi = {10.1038/s10038-018-0542-8}, author = {Liaqat, Khurram and Schrauwen, Isabelle and Raza, Syed Irfan and Lee, Kwanghyuk and Hussain, Shabir and Chakchouk, Imen and Nasir, Abdul and Acharya, Anushree and Abbe, Izoduwa and Umair, Muhammad and Ansar, Muhammad and Ullah, Irfan and Shah, Khadim and Bamshad, Michael J and Nickerson, Deborah A and Ahmad, Wasim and Leal, Suzanne M} } @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 {484, title = {Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment.}, journal = {BMC Med Genet}, volume = {19}, year = {2018}, month = {2018 07 20}, pages = {122}, abstract = {

BACKGROUND: Digenic inheritance is the simplest model of oligenic disease. It can be observed when there is a strong epistatic interaction between two loci. For both syndromic and non-syndromic hearing impairment, several forms of digenic inheritance have been reported.

METHODS: We performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease.

RESULTS: We found that this family displays digenic inheritance for two trans heterozygous missense mutations, one in PCDH15 [p.(Arg1034His)] and another in USH1G [p.(Asp365Asn)]. Both of these genes are known to cause autosomal recessive non-syndromic hearing impairment and Usher syndrome. The protein products of PCDH15 and USH1G function together at the stereocilia tips in the hair cells and are necessary for proper mechanotransduction. Epistasis between Pcdh15 and Ush1G has been previously reported in digenic heterozygous mice. The digenic mice displayed a significant decrease in hearing compared to age-matched heterozygous animals. Until now no human examples have been reported.

CONCLUSIONS: The discovery of novel digenic inheritance mechanisms in hereditary hearing impairment will aid in understanding the interaction between defective proteins and further define inner ear function and its interactome.

}, keywords = {Adult, Animals, Cadherins, Hearing Loss, Heterozygote, Humans, Male, Mechanotransduction, Cellular, Multifactorial Inheritance, Mutation, Nerve Tissue Proteins, Pakistan, Pedigree, Usher Syndromes, Young Adult}, issn = {1471-2350}, doi = {10.1186/s12881-018-0618-5}, author = {Schrauwen, Isabelle and Chakchouk, Imen and Acharya, Anushree and Liaqat, Khurram and Nickerson, Deborah A and Bamshad, Michael J and Shah, Khadim and Ahmad, Wasim 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 {100, title = {Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 08}, pages = {1223-7}, abstract = {

Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.

}, keywords = {Adolescent, Adult, Alopecia, Child, Female, Humans, Integrin beta Chains, Intellectual Disability, Male, Mutation, Missense, Pedigree, Phenotype, Protein Domains, Syndrome, Tooth Abnormalities}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.260}, author = {Ansar, Muhammad and Jan, Abid and Santos-Cortez, Regie Lyn P and Wang, Xin and Suliman, Muhammad and Acharya, Anushree and Habib, Rabia and Abbe, Izoduwa and Ali, Ghazanfar and Lee, Kwanghyuk and Smith, Joshua D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Ahmad, Wasim and Leal, Suzanne M} } @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} }