Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes
AbstractAs one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to tes...
Source: Human Genetics - September 7, 2023 Category: Genetics & Stem Cells Source Type: research
The natural history, clinical outcomes, and genotype –phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review
AbstractCongenital hearing loss affects one in 500 newborns. Sequence variations inOTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1 –8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship betweenOTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneousOTOF genotypes. Here, we present the first sy...
Source: Human Genetics - September 7, 2023 Category: Genetics & Stem Cells Source Type: research
Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes
AbstractAs one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to tes...
Source: Human Genetics - September 7, 2023 Category: Genetics & Stem Cells Source Type: research
CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct
AbstractEnlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants inSLC26A4. However, in European –Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles ofSLC26A4. We tested for the presence of variants inCHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles ofSLC26A4. In two families, NM_017780.4: c.3553A &g...
Source: Human Genetics - September 5, 2023 Category: Genetics & Stem Cells Source Type: research
Dyslexia-related loci are significantly associated with language and literacy in Chinese –English bilingual Hong Kong Chinese twins
This study explores the genetic overlap between Chinese and English word reading, vocabulary knowledge and spelling, and aims at replicating the association in a unique cohort of bilingual (Chinese –English) Hong Kong Chinese twins. Our result showed an almost complete genetic overlap in vocabulary knowledge (r2 = 0.995), and some genetic overlaps in word reading and spelling (r2 = 0.846, 0.687) across the languages. To investigate the region near rs2624839, we tested proxy SNPs (rs1005678, rs12632110 and rs12494414) at the population level (n = 305–308) and the within-twin level (n = 342–344 [171–1...
Source: Human Genetics - September 5, 2023 Category: Genetics & Stem Cells Source Type: research
CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct
AbstractEnlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants inSLC26A4. However, in European –Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles ofSLC26A4. We tested for the presence of variants inCHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles ofSLC26A4. In two families, NM_017780.4: c.3553A &g...
Source: Human Genetics - September 5, 2023 Category: Genetics & Stem Cells Source Type: research
Dyslexia-related loci are significantly associated with language and literacy in Chinese –English bilingual Hong Kong Chinese twins
This study explores the genetic overlap between Chinese and English word reading, vocabulary knowledge and spelling, and aims at replicating the association in a unique cohort of bilingual (Chinese –English) Hong Kong Chinese twins. Our result showed an almost complete genetic overlap in vocabulary knowledge (r2 = 0.995), and some genetic overlaps in word reading and spelling (r2 = 0.846, 0.687) across the languages. To investigate the region near rs2624839, we tested proxy SNPs (rs1005678, rs12632110 and rs12494414) at the population level (n = 305–308) and the within-twin level (n = 342–344 [171–1...
Source: Human Genetics - September 5, 2023 Category: Genetics & Stem Cells Source Type: research
A founder DBR1 variant causes a lethal form of congenital ichthyosis
We describe a distinct allelic disorder caused by a founder recessiveDBR1 variant in four families (DBR1(NM_016216.4):c.200A > G (p.Tyr67Cys)). Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. Patient-derived fibroblasts displayed the characteristic accumul ation of intron lariats in their RNA as revealed by targeted and untargeted analysis, in addition to a marked reduction of DBR1 on immunoblot analysis. We propose a novelDBR1-related developmental...
Source: Human Genetics - September 1, 2023 Category: Genetics & Stem Cells Source Type: research
Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia
AbstractMutations inTDP2, encoding tyrosyl-DNA phosphodiesterase 2, have been associated with a syndromal form of autosomal recessive spinocerebellar ataxia, type 23 (SCAR23). This is a very rare and progressive neurodegenerative disorder described in only nine patients to date, and caused by splice site or nonsense mutations that result in greatly reduced or absent TDP2 protein. TDP2 is required for the rapid repair of DNA double-strand breaks induced by abortive DNA topoisomerase II (TOP2) activity, important for genetic stability in post-mitotic cells such as neurons. Here, we describe a sibship that is homozygous for t...
Source: Human Genetics - September 1, 2023 Category: Genetics & Stem Cells Source Type: research
Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts
AbstractInadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes....
Source: Human Genetics - September 1, 2023 Category: Genetics & Stem Cells Source Type: research
A founder DBR1 variant causes a lethal form of congenital ichthyosis
We describe a distinct allelic disorder caused by a founder recessiveDBR1 variant in four families (DBR1(NM_016216.4):c.200A > G (p.Tyr67Cys)). Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. Patient-derived fibroblasts displayed the characteristic accumul ation of intron lariats in their RNA as revealed by targeted and untargeted analysis, in addition to a marked reduction of DBR1 on immunoblot analysis. We propose a novelDBR1-related developmental...
Source: Human Genetics - September 1, 2023 Category: Genetics & Stem Cells Source Type: research
Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts
AbstractInadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes....
Source: Human Genetics - September 1, 2023 Category: Genetics & Stem Cells Source Type: research
Colocalization of expression transcripts with COVID-19 outcomes is rare across cell states, cell types and organs
AbstractIdentifying causal genes at GWAS loci can help pinpoint targets for therapeutic interventions. Expression studies can disentangle such loci but signals from expression quantitative trait loci (eQTLs) often fail to colocalize —which means that the genetic control of measured expression is not shared with the genetic control of disease risk. This may be because gene expression is measured in the wrong cell type, physiological state, or organ. We tested whether Mendelian randomization (MR) could identify genes at loci in fluencing COVID-19 outcomes and whether the colocalization of genetic control of expression and ...
Source: Human Genetics - August 28, 2023 Category: Genetics & Stem Cells Source Type: research
Breakpoints in complex chromosomal rearrangements correspond to transposase-accessible regions of DNA from mature sperm
AbstractConstitutional complex chromosomal rearrangements (CCRs) are rare cytogenetic aberrations arising in the germline via an unknown mechanism. Here we analyzed the breakpoint junctions of microscopically three-way or more complex translocations using comprehensive genomic and epigenomic analyses. All of these translocation junctions showed submicroscopic genomic complexity reminiscent of chromothripsis. The breakpoints were clustered within small genomic domains with junctions showing microhomology or microinsertions. Notably, all of the de novo cases were of paternal origin. The breakpoint distributions corresponded ...
Source: Human Genetics - August 24, 2023 Category: Genetics & Stem Cells Source Type: research
