Biology subjects

Yntema, H. G.

Publications and source records attributed to Yntema, H. G..

3 recordsLinked to original sources

bioRxiv2026

Distinct mechanisms of CNV formation at the human 15q13.3 locus

Human chromosome 15q13.3 is a hotspot for recurrent pathogenic copy number variants (CNVs), which remain unresolved at the sequence level. We generated haplotype-resolved assemblies for 10 patient-parent trios and found that both the long ("BP4-BP5") and short ("CHRNA7") forms of 15q13.3 CNVs arise predominantly by non-allelic homologous recombination (NAHR) enabled by inversion polymorphisms. While most BP4-BP5 CNVs are structurally distinct, three breakpoints cluster in a 2 kbp PRDM9-enriched recombination hotspot. CHRNA7 CNVs originate from NAHR between CHRNA7-LCR repeats embedded within locus-spanning inversions and give rise to paired deletion/duplication events. Population analyses of 581 population haplotypes reveal at least 18 distinct structural haplotypes in 15q13.3 and more than 10-fold ancestry-stratification of BP4-BP5 CNV risk, where 68.4% of Europeans but only 5.1% of East Asians are predisposed. Comparison to six ape species indicates that the duplication architecture promoting instability expanded recently and is largely human-specific.

genetics↗

bioRxiv2020

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 exome-sequences of healthy, genetically-unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal recessive (AR) genes, and that 0.8-1% of European couples are at-risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins, but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

genetics↗

bioRxiv2019

A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss

Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss. We identified an in-frame deletion of 12 nucleotides in RIPOR2 as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average age of onset of 30.6 years (SD 14.9 years, range 0-70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localization of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wildtype protein. Strikingly, the RIPOR2 variant is present in 18 of 22,952 individuals not selected for hearing loss in the Southeast Netherlands. Collectively, these data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.

genetics↗