PCSK5 was first reported in relation to autosomal dominant syndromic congenital heart disease in 2008 (Szumska et al., PMID: 18519639). Structural congenital heart defects (CHD) has been observed with other syndromic features such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal anomalies, and limb abnormalities), Caudal regression syndrome, Currarino syndrome, heterotaxy, and cleft lip/palate in patients carrying PCSK5 variants. At least ten unique variants (8 missense, 1 in-frame indel, 1 nonsense) have been reported in eleven individuals with syndromic CHD (PMID: 18519639, 24416387, 26055999, 30896870, 33131162). Of these, only the proband with the in-frame indel variant was scorable; the remaining variants had high minor allele frequencies in gnomAD v4.1.0. However, the proband was not scored either due to uncertainties of the pathogenicity of PCSK5 variants in syndromic CHD. This gene-disease relationship is supported by evidence of biochemical function, functional alteration, and an ENU-induced recessive mouse model replicating many of the VACTERL phenotypes (PMIDs: 21480163, 28446132,18519639). In summary, the evidence supporting the relationship between PCSK5 and autosomal dominant syndromic CHD has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role PCSK5 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date April 1st, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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