Biology in balance: human diploid genome integrity, gene dosage, and genomic medicine

Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability

“…“Mirror trait” conditions are special allelic series that are defined as resulting from reciprocal genetic/genomic variants (e.g., duplication versus deletion CNV, LoF versus GoF) of the same gene/loci and can cause the observed phenotypes in individuals to appear at the opposite ends of a phenotypic spectrum (e.g., short stature versus tall stature). 57 , 64 As we addressed previously, biallelic LoF variants of NPR2 were frequently reported, causing AMDM characterized by short-limbed short stature. However, a few of the heterozygous missense variant and in-frame deletion alleles of NPR2 were also reported to cause AD epiphyseal chondrodysplasia, Miura type (ECDM; MIM: 615923 ), characterized by tall stature, arachnodactyly, and long/broad halluces and long metatarsals because of a GoF (potentially a hypermorphic allele) that results in overactivity of guanylate cyclase ( Figure S6 ).…”

“…This duplicated allele was brought into homozygosity in the proband with GWC through IBD, not IBS, resulting in four genomic copies of the gene and genomic duplication interval ( Figures 4 A and 4C), a gene copy number identical to the heterozygous triplication mentioned above. 57 …”

“…Such genes may be subject to a gene dosage effect and may be dosage sensitive, and this aspect may serve as the major determinant of its pathogenicity resulting in haploinsufficient and triplosensitive traits and even mirror traits. 57 CNV studies of dosage-sensitive genes have contributed significantly to the progress of disease gene discovery and genomic instability/genome integrity mutagenesis; i.e., SV mutagenesis of the human genome.…”

The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits

“…This unique combination of rare variants located in ROH regions in each individual genome to generate disease haplotypes characteristic of their recent family lineage, pedigree, or clan may explain their clinical phenotypic features and thereby their pathogenicity, providing further support for the Clan Genomics hypothesis (Lupski, 2021; 2022; Lupski et al ., 2011) and potentially illuminating La Reunion paradox. This paradox was reported in previous studies that documented six different Limb-Girdle Muscular Dystrophy 2A (LGMD2A) gene mutations in a small genetic isolate from La Reunion Island, in which all affected individuals from La Reunion were hypothesized to share a common haplotype (Beckmann, 1996; Richard et al, 1995; Zlotogora et al, 1996); however, paradoxically, haplotype analysis demonstrated multiple haplotypes associating with disease (Allamand et al, 1995).…”

“…chronic kidney disease, scoliosis, arthrogryposis, developmental delay and intellectual disability), suggesting that a substantial proportion of seemingly common, complex conditions may in fact represent a combination of individually rare, Mendelian disease traits (Groopman et al, 2020; Karaca et al, 2015; Mitani et al, 2021; Pehlivan et al, 2019; Wu et al, 2015). These observations, and the elucidation of the de novo mutation contribution to rare disease across a range of phenotypes referred for study in diagnostic laboratories (Posey et al, 2019; Scott et al, 2021; Yang et al, 2013; Yang et al, 2014), lend support to the Clan Genomics hypothesis, which predicts that a disproportionate fraction of human disease is driven by new mutations that, by definition, are unique to a studied family or clan (Lupski, 2021; 2022; Lupski et al, 2011).…”