Systematic analysis of homozygous autosomal copy number losses in exomes improves diagnostic yield and uncovers ultra-rare recessive disorders

Systematic detection of homozygous deletions from exome data, revealing recessive disease genes

A systematic approach to detect homozygous copy number losses was applied to exome data from 2,021 Indian patients with suspected Mendelian disorders. Filtering based on genomic position loss-count reduced 42,386 candidate losses to 1,224 rare calls, enabling 10 new diagnoses among 240 unsolved cases — a two-fold increase in diagnostic yield from homozygous deletions. The analysis identified biallelic FILIP1 and FAM177A1 variants (syndromic arthrogryposis and a neuromuscular disorder), validating recently reported entities. It also revealed that biallelic loss-of-function TFCP2L1 variants cause chronic kidney disease and VPS36 variants a severe recessive neurodevelopmental disorder with microcephaly, corpus callosum agenesis, and early death.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This paper concretely illustrates the exome/genome editorial line: the data is already captured by WES, and it is the detection method for often-overlooked homozygous deletions that unlocks the diagnosis. Leveraging populations underrepresented in public databases (here India) is a powerful lever for ultra-rare recessive disorders. An approach transferable to any laboratory with accumulated unsolved exomes.