Recessive and dominant inheritance due to variants at a single locus

Monoallelic and biallelic variation at a single locus may lead to either similar phenotypes, different severity of a phenotype along a clinical continuum, distinct phenotypes, or susceptibility to disease versus fully penetrant Mendelian disease. Molecularly, genotype-phenotype correlations in allelic series have been attributed to multiple mechanisms, including type of allele (i.e., antimorph, hypomorph, neomorph or null); localization of variants in specific functional domains, degree of pathogenicity, or escape versus trigger of nonsense mediated decay. Through exome sequencing and chromosomal microarray analysis of individuals with primarily neurological manifestations, we have identified several genes with variants following autosomal dominant (AD) and recessive (AR) inheritance patterns at the same locus. For example, monoallelic variants in ATAD3A, encoding a mitochondrial protein, lead to developmental delay, optic atrophy, axonal neuropathy and cardiomyopathy via a dominant-negative mechanism; whereas biallelic deletions including ATAD3A and mediated by nonallelic homologous recombination (NAHR), result in an infantile-lethal null phenotype. We recently identified the NAHR-mediated reciprocal duplication between ATAD3 paralogs, and showed that this results in alteration of the C-terminus and exerts a dominant-negative effect with a phenotype similar to biallelic deletions. Additional genes with AD/AR inheritance include EMC1, MARS, MYLPF, MAPRE2 and CDON. We attempt to investigate allelic spectrums of disease by exploring the underlying pathogenetic mechanisms in cellular and animal models. Moreover, we highlight the importance of recognizing that different patterns of inheritance may occur with variants at a single locus, in order to avoid this pitfall in interpretation of next-generation sequencing data and to maximize novel gene discovery.