The Diverse Genetic Landscape of Hearing Impairment in South African Families.

To elucidate the genetic etiology of hearing impairment (HI) in South Africa, 45 nonsyndromic HI (NSHI) and syndromic HI (SHI) families with ≥ 2 affected members were analyzed. Exome and sanger sequencing were used to identify causal genes. For NSHI, 14 of 24 families segregated variants in NSHI genes, that is, CDH23, GJB2, MITF, MYO7A, MYO15A, PCDH15, POU3F4, REST, SLC26A4, TMPRSS3, and WFS1.

Exome sequencing revealed a novel homozygous variant in TRMT61 A in a multiplex family with atypical Cornelia de Lange Syndrome from Rwanda.

Background: In 30% of patients who exhibit the clinical profile of Cornelia de Lange Syndrome (CdLS), the genetic cause remains undetermined. This proportion tends to be higher in low-resource settings including Africa. We performed a molecular characterization of CdLS in a multiplex Rwandan family.

Bi-Allelic Variant Identified with Exome Sequencing in a Consanguineous Multiplex Ghanaian Family Segregating Non-Syndromic Hearing Loss.

Genetic studies and phenotypic expansion of hearing loss (HL) for people living in Africa are greatly needed. We evaluated the clinical phenotypes of three affected siblings presenting non-syndromic (NS) HL and five unaffected members of a consanguineous Ghanaian family. Analysis of exome sequence data was performed for all affected and one unaffected family members.

Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis.

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL.

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits.

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time.

Purpose: The Clinical Genome Resource (ClinGen) Hearing Loss Gene Curation Expert Panel was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semiquantitative framework. ClinGen mandates the timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong every 2 to 3 years.

Methods: Thirty-five GDRs met the criteria for recuration within 2 years of original curation.

A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.

DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive.

THBS1 is a new autosomal recessive non-syndromic hearing impairment gene.

Background: Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI).

Biallelic variants in cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder which is clinically and genetically heterogeneous. Genome sequencing identified biallelic variants in individuals from five unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small and, a more pronounced reduction of, the large mitochondrial ribosomal subunits.

Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders.

While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing.

Heterogeneous genetic patterns in bilateral perisylvian polymicrogyria: insights from a Finnish family cohort.

Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all malformations of cortical development. Bilateral perisylvian polymicrogyria is characterized by an excessive folding of the cerebral cortex and abnormal cortical layering. Notable clinical features include upper motoneuron dysfunction, dysarthria and asymmetric quadriparesis.

A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.

Bilateral perisylvian polymicrogyria (BPP) is a structural malformation of the cerebral cortex that can be caused by several genetic abnormalities. The most common clinical manifestations of BPP include intellectual disability and epilepsy. Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a protein that interacts with the fragile X mental retardation protein (FMRP).

A loss of function variant in AGPAT3 underlies intellectual disability and retinitis pigmentosa (IDRP) syndrome.

Intellectual disability (ID) and retinal dystrophy (RD) are the frequently found features of multiple syndromes involving additional systemic manifestations. Here, we studied a family with four members presenting severe ID and retinitis pigmentosa (RP). Using genome wide genotyping and exome sequencing, we identified a nonsense variant c.

Nonsense variant in a consanguineous family expands the phenotype of KPTN gene-related syndrome to include hearing impairment.

A short report with two affected siblings from consanguineous family born with intellectual disability, motor disability, language deficit, and hearing impairment and found to carry biallelic nonsense variant in KPTN gene known to be associated with KPTN gene related syndrome.

A Novel Variant in Underlying Cohen Syndrome.

Pathogenic variants in vacuolar protein sorting 13 homolog B () cause Cohen syndrome (CS), a clinically diverse neurodevelopmental disorder. We used whole exome and Sanger sequencing to identify disease-causing variants in a Pakistani family with intellectual disability, microcephaly, facial dysmorphism, neutropenia, truncal obesity, speech delay, motor delay, and insomnia. We identified a novel homozygous nonsense variant c.

The genetic contribution of the X chromosome in age-related hearing loss.

Age-related (AR) hearing loss (HL) is the most common sensory impairment with heritability of 55%. The aim of this study was to identify genetic variants on chromosome X associated with ARHL through the analysis of data obtained from the UK Biobank. We performed association analysis between self-reported measures of HL and genotyped and imputed variants on chromosome X from ∼460,000 white Europeans.

Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.

Hereditary deafness and retinal dystrophy are each genetically heterogenous and clinically variable. Three small unrelated families segregating the combination of deafness and retinal dystrophy were studied by exome sequencing (ES). The proband of Family 1 was found to be compound heterozygous for NM_004525.

Rare-variant association analysis reveals known and new age-related hearing loss genes.

Age-related (AR) hearing loss (HL) is a prevalent sensory deficit in the elderly population. Several studies showed that common variants increase ARHL susceptibility. Here, we demonstrate that rare-variants play a crucial role in ARHL etiology.

Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study.

Otosclerosis is one of the most common causes of hearing loss in young adults. It has a prevalence of 0.3-0.

A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana.

Background: Childhood hearing impairment (HI) is genetically heterogeneous with many implicated genes, however, only a few of these genes are reported in African populations.

Methods: This study used exome and Sanger sequencing to resolve the possible genetic cause of non-syndromic HI in a Ghanaian family.

Results: We identified a novel variant c.