Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Carboxypeptidase E (CPE) encodes an essential prohormone processing enzyme that converts proneuropeptides and propeptide hormones to their bioactive forms and is widely expressed in the endocrine and central nervous systems. Biallelic loss-of-function CPE variants have been implicated in a novel autosomal recessive Mendelian disorder, Blakemore-Durmaz-Vasileiou (BDV) syndrome, characterized by childhood-onset morbid obesity, neurodevelopmental delay, hypogonadotropic hypogonadism, and hypothyroidism. The clinical overlap with Prader-Willi syndrome led to initial misdiagnoses before genetic confirmation.
To date, four individuals from three unrelated consanguineous families harboring homozygous truncating CPE variants have been described (PMID:34383079). These include two Syrian siblings, one Egyptian proband, and one Pakistani proband, all presenting with severe obesity and global developmental delay. Endocrine anomalies such as hypogonadotropic hypogonadism and hypothyroidism were universally observed. Prader-Willi syndrome was excluded in all cases prior to exome sequencing. Variant curation relied on research-level exome datasets and segregation analysis. The phenotypic consistency across diverse ethnic backgrounds underscores a robust genotype–phenotype correlation.
The inheritance mode is autosomal recessive, with homozygous CPE variants segregating with disease in affected families. A single additional affected relative (the Syrian sibling) confirmed segregation of the c.361C>T (p.Arg121Ter) variant within one family. No pathogenic variants were observed in heterozygous parents, who remained asymptomatic. This inheritance pattern aligns with loss-of-function as the primary mechanism. Segregation data and absence of variants in population databases support pathogenicity under ClinGen guidelines. Collectively, these findings provide strong genetic evidence for association.
The variant spectrum in BDV syndrome is currently confined to truncating alleles. The recurrent homozygous variant c.361C>T (p.Arg121Ter) was identified in three individuals, and c.994del (p.Ser333AlafsTer22) in one (PMID:34383079). Both changes are predicted to trigger nonsense-mediated decay or yield truncated, nonfunctional proteins. Computational modeling of all possible missense alterations indicates high domain conservation and intolerance to missense disruption, suggesting that other variant classes may also be deleterious. No missense, splice, or structural variants have yet been definitively linked to BDV syndrome. Continued case ascertainment may reveal further allelic heterogeneity.
Functional evidence derives from the fat/fat mouse model, which carries a Ser202Pro Cpe mutation and develops obesity and hyperglycemia due to virtual absence of CPE activity in pancreatic islets and pituitaries (PMID:7663508). In vitro studies of Ser202Pro mutants confirm loss of secretion and enzymatic function, while conservation analyses validate critical active-site residues. Although direct functional assays of human truncating variants are pending, the concordant animal and cellular data support haploinsufficiency and loss-of-function mechanisms. This body of work fulfills moderate functional evidence criteria under ClinGen.
In summary, homozygous truncating CPE variants cause a clinically recognizable autosomal recessive BDV syndrome defined by morbid obesity, neurodevelopmental delay, hypogonadotropic hypogonadism, and hypothyroidism. Strong genetic and moderate functional evidence establish a definitive gene–disease association, with no conflicting reports to date. Inclusion of CPE in diagnostic gene panels for early-onset obesity with neuroendocrine features will facilitate timely diagnosis and management. Further studies are warranted to explore the role of missense alleles and potential targeted therapies. Identification of homozygous CPE loss-of-function variants definitively establishes CPE as causative for BDV syndrome, supporting its clinical utility in genetic diagnostics.
Gene–Disease AssociationStrong4 probands, 3 families, homozygous truncating variants and segregation ([PMID:34383079]) Genetic EvidenceStrong4 individuals with biallelic loss-of-function variants and segregation in a sibling pair ([PMID:34383079]) Functional EvidenceModerateFat/fat Cpe mouse model recapitulates obesity and prohormone processing defects; conservation analyses support loss-of-function ([PMID:7663508]) |