3.9 Article

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

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ELSEVIER
DOI: 10.1016/j.xhgg.2022.100132

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资金

  1. National Human Genome Research Institute (NHGRI)
  2. National Heart, Lung, and Blood Institute (NHBLI) [UM1 HG006542]
  3. Baylor College of Medicine Genomics Research to Elucidate the Genetics of Rare disease [BCM-GREGoR] [U01 HG011758]
  4. National Institute of Neurological Disorders and Stroke (NINDS) [R35NS105078]
  5. Muscular Dystrophy Association (MDA) [512848]
  6. Spastic Paraplegia Foundation (SPF)
  7. NHGRI [K08 HG008986]
  8. International Rett Syndrome Foundation (IRSF) [3701-1]

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In a study of 18 families with congenital limb malformations, variants associated with disease traits were identified through family-based genomics, highlighting the complexity of genetic pathogenesis underlying these anomalies. The findings suggest a novel contributory genetic mechanism in limb birth defects and provide insights into the interconnections among allelic series, clinical severity, and reduced penetrance.
Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported disease trait associated loci: BHLHA9, GLI3, HOXD cluster, HOXD13, NPR2, and WNT10B. Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu-mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9-related CLM spectrum.

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