ABL1 – Congenital Heart Defects and Skeletal Malformations Syndrome

Congenital heart defects and skeletal malformations syndrome (CHDSKM; MONDO:0060532) is an autosomal dominant disorder marked by dysmorphic facial features, congenital cardiac lesions, failure to thrive, and skeletal anomalies. ABL1 germline missense variants were first implicated in CHDSKM in 2017, with both de novo and familial occurrences (PMID:28288113).

Genetic evidence includes a cohort of six patients harboring de novo missense variants (c.407C>T, c.746C>T, c.1573G>A, and recurrent c.1066G>A) and three affected individuals from three families with c.734A>G (p.Lys245Arg) segregating with disease (PMID:32643838; PMID:36949638; PMID:39887622). To date, eight probands and five affected relatives have been reported, encompassing missense substitutions clustered in regulatory domains of ABL1.

Segregation analysis demonstrated co-segregation of c.734A>G (p.Lys245Arg) in three multigenerational families and recurrent observation of p.Ala356Thr in unrelated cases, supporting pathogenicity. Functional assays of p.Tyr245Cys and p.Ala356Thr expressed in HEK293T cells revealed increased ABL1 tyrosine phosphorylation and kinase activity, consistent with a gain-of-function mechanism (PMID:28288113).

Experimental data corroborate that CHDSKM arises from enhanced ABL1 catalytic activity rather than haploinsufficiency. Animal models and developmental studies of Abl1 knockout mice further underscore the critical role of precise ABL1 regulation in cardiogenesis and skeletogenesis.

No conflicting reports have been published to date. The cumulative genetic and functional evidence satisfies ClinGen criteria for a Definitive gene-disease relationship.

Key Take-home: Germline ABL1 gain-of-function variants cause autosomal dominant CHDSKM with consistent cardiac and skeletal manifestations, warranting early molecular testing and surveillance of aortic root dimensions.

References

• Nature Genetics • 2017 • Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. PMID:28288113
• Human Mutation • 2020 • The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome. PMID:32643838
• American Journal of Medical Genetics Part A • 2023 • ABL1-related congenital heart defects and skeletal malformations syndrome in a patient from Sub-Saharan Africa: A case report highlighting novel cardiac features. PMID:36949638
• American Journal of Medical Genetics Part A • 2025 • A Novel Missense Mutation of the ABL1 Gene in a Child With Congenital Heart Defects and Skeletal Malformations Syndrome. PMID:39887622

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