TY  - JOUR
A1  - Bahena, Paulina
A1  - Daftarian, Narsis
A1  - Maroofian, Reza
A1  - Linares, Paola
A1  - Villalobos, Daniel
A1  - Mirrahimi, Mehraban
A1  - Rad, Aboulfazl
A1  - Doll, Julia
A1  - Hofrichter, Michaela A. H.
A1  - Koparir, Asuman
A1  - Röder, Tabea
A1  - Han, Seungbin
A1  - Sabbaghi, Hamideh
A1  - Ahmadieh, Hamid
A1  - Behboudi, Hassan
A1  - Villanueva-Mendoza, Cristina
A1  - Cortés-Gonzalez, Vianney
A1  - Zamora-Ortiz, Rocio
A1  - Kohl, Susanne
A1  - Kuehlewein, Laura
A1  - Darvish, Hossein
A1  - Alehabib, Elham
A1  - La Arenas-Sordo, Maria de Luz
A1  - Suri, Fatemeh
A1  - Vona, Barbara
A1  - Haaf, Thomas
T1  - Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment
JF  - Human Genetics
N2  - Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf-blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf-blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.
KW  - Usher syndrome
KW  - hearing impairment
KW  - combined retinal dystrophy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267750
SN  - 1432-1203
VL  - 141
IS  - 3-4
ER  - 
TY  - JOUR
A1  - Doll, Julia
A1  - Vona, Barbara
A1  - Schnapp, Linda
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Khan, Saadullah
A1  - Muhammad, Noor
A1  - Alam Khan, Sher
A1  - Nawaz, Hamed
A1  - Khan, Ajmal
A1  - Ahmad, Naseer
A1  - Kolb, Susanne M.
A1  - Kühlewein, Laura
A1  - Labonne, Jonathan D. J.
A1  - Layman, Lawrence C.
A1  - Hofrichter, Michaela A. H.
A1  - Röder, Tabea
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Graves, Tyler D.
A1  - Kong, Il-Keun
A1  - Nanda, Indrajit
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
T1  - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families
JF  - Genes
N2  - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
KW  - genetic diagnosis
KW  - consanguinity
KW  - genome-wide linkage analysis
KW  - hearing loss
KW  - Pakistan
KW  - exome sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293
SN  - 2073-4425
VL  - 11
IS  - 11
ER  -