Abstract
The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.
Highlights
The repertoire of diagnostic tests in human genetics is as diverse as the types of genetic alterations they were developed to detect (Berisha et al 2020)
Potentially pathogenic heterozygous coding variants of genes associated with a recessive limb phenotype in individuals featuring at least a partial overlap with that phenotype, we screened for in trans conserved non-coding variants with a MAF < 3% affecting the same topologically associating domain (TAD)
In individual I10 with bilateral upper and lower limb ectrodactyly, we identified an inversion of 105 kb flanked by two deletions at the split-hand foot malformation locus 3 (SHFM3) on chr10q24 inherited from his unaffected mother (Fig. 1, Supplementary Fig. 6)
Summary
The repertoire of diagnostic tests in human genetics is as diverse as the types of genetic alterations they were developed to detect (Berisha et al 2020). Through the development of Generation Sequencing technologies (NGS) sequencing has become several orders of magnitude faster and cheaper. This has led to an enormous increase in the efficiency of genetic testing (Levy and Myers 2016). NGS quickly found its way from research applications to the clinic: today, panel and exome sequencing are elements. Stefan Mundlos and Malte Spielmann shared senior authorship
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