Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants

Area of Science:

• Genetics
• Genomics
• Rare Diseases

Background:

• Identifying pathogenic noncoding variants is a significant challenge in genetic diagnostics.
• Individuals with developmental disorders (DDs) often have a single protein-altering variant in a recessive gene, but the role of noncoding variants is unclear.

Purpose of the Study:

• To investigate the prevalence and diagnostic utility of pathogenic noncoding variants as a second hit in individuals with undiagnosed developmental disorders.
• To develop a systematic approach for identifying compound heterozygous coding/noncoding variants.

Main Methods:

• Analyzed 4073 trio probands from the 100,000 Genomes Project with rare heterozygous protein-altering variants in recessive DD-associated genes.
• Identified rare noncoding variants in trans (introns, UTRs, promoters, enhancers) and performed clinical evaluation and functional testing.

Main Results:

• Identified 3761 rare heterozygous variants in recessive DD genes in 2430 probands.
• Found at least one rare noncoding variant in trans in 1366 (36.3%) of these cases.
• Identified likely diagnoses in 3 probands (GAA, NPHP3, PKHD1) and candidate diagnoses in 3 more, highlighting the diagnostic potential.

Conclusions:

• A systematic approach was developed to uncover new diagnoses involving compound heterozygous coding/noncoding variants.
• This mechanism, while rare, is a significant contributor to developmental disorders and aids in genetic diagnosis.