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Some Developmental Disorders Caused by Recessive Coding Variants

NEW YORK (GenomeWeb) – Recessive coding variants contribute to a portion of developmental disorders, though less than dominant variants do, according to a new study.

Researchers from the Deciphering Developmental Disorders study had previously estimated that 40 percent to 45 percent of individuals with developmental disorders harbored causal de novo coding mutations. They have now extended their analysis to determine the effect of recessive variants on these disorders as well.

A team led by the Wellcome Trust Sanger Center's Jeffrey Barrett examined recessive coding variation within more than 6,000 families from the DDD study, including patients of European and Pakistani ancestry. As they reported today in Science, the researchers found varying contributions of recessive coding variants to the risk of developmental disorders between the two populations and identified two new recessive disease-linked genes.

"Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed non-consanguineous individuals, and that the role of noncoding variants, incomplete penetrance and polygenic mechanisms need further exploration," Barrett and his colleagues wrote in their paper.

This cohort included 6,040 individuals from the British Isles — including 5,684 people of European descent and 356 people of Pakistani ancestry — with developmental disorders. The researchers noted that the affected individuals had heterogeneous clinical features, though the symptoms were broadly similar across the European and Pakistani patients. These individuals and their parents underwent exome sequencing.

The researchers investigated the number of rare biallelic genotypes within their cohort and found no significant burden of biallelic genotypes among those 1,389 probands with a likely diagnostic de novo, inherited dominant, or X-linked variant. The remaining, undiagnosed individuals, the researchers noted, were more likely to have a recessive variant contributing to their disease.

Probands of Pakistani ancestry had more rare biallelic genotypes than probands of European ancestry, which the researchers expected due to higher autozygosity in that population. In addition, they found an enrichment of biallelic loss-of-function genotypes in undiagnosed individuals of both European and Pakistani ancestry, and noted a higher recessive burden among known developmental disorder-linked genes.

In all, the researchers estimated that 3.6 percent of the 5,684 European ancestry affected individuals have a recessive coding diagnosis, as compared to 49.9 percent with a de novo coding diagnosis, while 30.9 percent of the affected individuals  of Pakistani ancestry have a recessive coding diagnosis, as compared to 29.8 percent with a de novo coding diagnosis. They again attributed this difference between groups to variations in autozygosity.

The researchers also identified variants in two genes not previously associated with developmental disorders.

In particular, five individuals from their cohort had missense variants in EIF3F, as did four other individuals who had been excluded from their analysis. EIF3F encodes a subunit of the eIF3 complex, which negatively regulates translation. When the researchers edited iPSC lines to be either heterozygous or homozygous for this variant, they found a 27 percent reduction in EIF3F protein levels in the homozygous cells, as compared to heterozygous or wild-type cells, as well as lowered cell proliferation rates.

Similarly, three individuals had biallelic loss-of-function alterations affecting KDM5B, while another individual was a compound heterozygous for a splice site variant and a deletion affecting KDM5B. KDM5B encodes a histone H3K4 demethylase. Analysis of a mouse loss-of-function model of KDM5B indicated that KDM5B-null mice exhibited lowered viability and expressed behavioral changes, such as increased anxiety, lower sociability, and worse memory.

The researchers estimated that uncovering all recessive developmental disorder genes would enable them to diagnose about 5.2 percent of a combined European and Pakistani cohort, while identifying dominant genes would allow them to diagnose about 48 percent of individuals.