@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 {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} }