@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 {679, title = {Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Sep}, pages = {1456-1465}, abstract = {

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.

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0417-2}, author = {Chakchouk, Imen and Zhang, Di and Zhang, Zhihui and Francioli, Laurent C and Santos-Cortez, Regie Lyn P and Schrauwen, Isabelle and Leal, Suzanne M} } @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 {664, title = {Heterozygosity mapping for human dominant trait variants.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 07}, pages = {996-1004}, abstract = {

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.

}, issn = {1098-1004}, doi = {10.1002/humu.23765}, author = {Imai-Okazaki, Atsuko and Li, Yi and Horpaopan, Sukanya and Riazalhosseini, Yasser and Garshasbi, Masoud and Mosse, Yael P and Zhang, Di and Schrauwen, Isabelle and Sharma, Aarushi and Fann, Cathy S J and Leal, Suzanne M and Lathrop, Mark and Ott, Jurg} } @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 {485, title = {A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {471-478}, abstract = {

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

}, keywords = {Adolescent, Adult, Animals, Child, Disease Models, Animal, Ear, Inner, Female, Genes, Dominant, Genes, Recessive, Hearing Loss, Hearing Loss, Sensorineural, Homozygote, Humans, LIM-Homeodomain Proteins, Male, Mice, Mutation, Missense, Pedigree, Transcription Factors, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-018-1899-7}, author = {Schrauwen, Isabelle and Chakchouk, Imen and Liaqat, Khurram and Jan, Abid and Nasir, Abdul and Hussain, Shabir and Nickerson, Deborah A and Bamshad, Michael J and Ullah, Asmat and Ahmad, Wasim and Leal, Suzanne M} } @article {62, title = {A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {909-918}, abstract = {

The proteins encoded by TELO2, TTI1, and TTI2 interact to form the TTT complex, a co-chaperone for maturation of the phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Here we report six affected individuals from four families with intellectual disability (ID) and neurological and other congenital abnormalities associated with compound heterozygous variants in TELO2. Although their fibroblasts showed reduced steady-state levels of TELO2 and the other components of the TTT complex, PIKK functions were normal in cellular assays. Our results suggest that these TELO2 missense variants result in loss of function, perturb TTT complex stability, and cause an autosomal-recessive syndromic form of ID.

}, keywords = {Adolescent, Carrier Proteins, Child, Female, Humans, Intellectual Disability, Male, Molecular Chaperones, Pedigree, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Telomere-Binding Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.014}, author = {You, Jing and Sobreira, Nara L and Gable, Dustin L and Jurgens, Julie and Grange, Dorothy K and Belnap, Newell and Siniard, Ashley and Szelinger, Szabolcs and Schrauwen, Isabelle and Richholt, Ryan F and Vallee, Stephanie E and Dinulos, Mary Beth P and Valle, David and Armanios, Mary and Hoover-Fong, Julie} }