ITGB4 and Aplasia Cutis Congenita

ITGB4 has been implicated in autosomal recessive aplasia cutis congenita (ACC). A single purebred Charolais calf homozygous for a 4.4 kb deletion spanning exons 17–22 of ITGB4 presented with neonatal skin fragility consistent with epidermolysis bullosa junctionalis (PMID:25890340). In humans, two siblings from one family with ACC type VI exhibited skin absence, limb deformities, and congenital heart malformations and were compound heterozygous for c.794dupC (p.Ala266SerfsTer5) and c.1860G>A (p.Ala620=) in ITGB4; carrier testing and preimplantation genetic diagnosis prevented recurrence (PMID:36458141).

No additional affected relatives segregating these variants have been reported, and the human variant spectrum for ACC is limited to a single frameshift allele. Functional studies directly in ACC are lacking; however, the bovine loss-of-function model supports a haploinsufficiency mechanism disrupting dermal–epidermal adhesion. Clinical validity is therefore assessed as Limited.

Key Take-home: Biallelic loss-of-function ITGB4 variants cause autosomal recessive ACC type VI, and genetic testing including PGD-M offers clinical utility in at-risk families.

References

• Frontiers in pediatrics • 2022 • A successful case of preimplantation genetic testing for monogenic disorder for aplasia cutis congenita. PMID:36458141
• BMC veterinary research • 2015 • DNA-based diagnosis of rare diseases in veterinary medicine: a 4.4 kb deletion of ITGB4 is associated with epidermolysis bullosa in Charolais cattle PMID:25890340

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