IHH – Brachydactyly type A1

Brachydactyly type A1 (BDA1) is an autosomal dominant skeletal dysplasia characterized by shortening or absence of the middle phalanges of the hands and feet. The Indian Hedgehog gene (IHH) encodes a secreted ligand critical for endochondral ossification and chondrocyte proliferation. Pathogenic heterozygous variants in IHH disrupt ligand processing, receptor interaction, and downstream signaling, leading to the BDA1 phenotype.

IHH-related BDA1 follows an autosomal dominant inheritance pattern with high penetrance. A novel c.472C>T (p.Arg158Cys) variant co-segregated in six affected members of a Swedish pedigree (Zmax 3.42) ([PMID:19464397]). Additional heterozygous missense variants, including c.299A>G (p.Asp100Gly) in a five-generation Chinese family (8 affected) ([PMID:32209048]), and founder mutations c.298G>C (p.Asp100His) identified in two unrelated Drinkwater families, further establish the recurrent involvement of IHH in BDA1.

The variant spectrum encompasses primarily missense changes clustered in the N-terminal signaling domain (e.g., Glu95, Asp100, Glu131, Arg158). These variants co-segregate with disease status and exhibit perfect penetrance for the phalangeal phenotype. Recurrent and founder alleles at Asp100 and Glu95 highlight mutational hotspots critical for ligand–receptor binding.

Functional assays in C3H10T1/2 cells demonstrate that BDA1-associated IHH mutations (p.Glu95Lys, p.Asp100Glu, p.Glu131Lys) severely impair induction of downstream targets Ptch1 and Gli1, and alter expression of novel effectors Sostdc1, Penk1, and Igfbp5 ([PMID:20024692]). Structural and temperature-sensitivity studies reveal destabilization of the IhhN fragment and reduced binding to Patched1 ([PMID:21537345]). Recent secretion assays confirm that both N- and C-terminal domain variants significantly reduce ligand availability, linking defective processing to short stature and skeletal defects ([PMID:38917024]).

No studies have refuted the IHH–BDA1 association. Variants in the C-terminal domain may present with mild or variable brachydactyly and short stature, expanding the phenotypic spectrum beyond classical BDA1. However, all pathogenic IHH variants consistently impair Hedgehog signaling.

Collectively, extensive case-level and functional data definitively establish heterozygous IHH variants as the cause of autosomal dominant BDA1. Genetic testing of IHH enables accurate diagnosis, informs recurrence risk, and guides clinical management, including early recognition of osteoarthritis and growth abnormalities.

References

• European Journal of Medical Genetics • 2009 • Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene. [PMID:19464397]
• BMC Medical Genetics • 2020 • A novel variant of IHH in a Chinese family with brachydactyly type A1. [PMID:32209048]
• Human Genetics • 2002 • A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved. [PMID:12384778]
• Cellular & Molecular Biology Letters • 2010 • Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling. [PMID:20024692]
• Cell Research • 2011 • Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels. [PMID:21537345]
• European Journal of Endocrinology • 2024 • Variants in both the N- or C-terminal domains of IHH lead to defective secretion causing short stature and skeletal defects. [PMID:38917024]

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