MEGF8 – Carpenter syndrome

MEGF8 encodes a large transmembrane protein containing multiple epidermal-growth-factor–like domains that modulates hedgehog and nodal signalling during embryogenesis. Carpenter syndrome is a rare autosomal recessive multiple-congenital-malformation disorder defined by multisuture craniosynostosis, polysyndactyly, and frequent obesity, umbilical hernia, cryptorchidism, and congenital heart disease. A subset of cases exhibits defective left–right patterning, including situs inversus, dextrocardia, and transposition of the great arteries, indicating perturbation of laterality pathways ([PMID:23063620]).

Autosomal recessive MEGF8 variants have been identified in 15 affected individuals from nine families with Carpenter syndrome–like phenotypes, supporting strong clinical validity. Five probands harbor biallelic MEGF8 alleles in the initial cohort ([PMID:23063620]), and an additional eight individuals from six families with MEGF8-associated CRPT2 expand the total to 15 probands ([PMID:38760421]). No consanguineous segregation beyond affected sib pairs has been reported.

The variant spectrum comprises 11 distinct alleles: six truncating (nonsense or splice-site) and five non-synonymous (missense or small indel) changes. Notably, recurrent hypomorphic alleles such as c.3577C>T (p.Arg1193Ter) and in-frame deletions suggest that complete loss of MEGF8 is incompatible with viability. All reported variants occur in trans, and no individual carries two predicted complete loss-of-function alleles.

Functional studies in zebrafish demonstrate that human missense alterations provide only weak rescue of early gastrulation defects induced by megf8 knockdown, indicating partial loss of activity. Megf8 mouse mutants recapitulate laterality defects observed in humans, including abnormal heart morphology and heterotaxy, confirming concordant in vivo phenotypes ([PMID:23063620]; [PMID:19218456]).

Mechanistically, MEGF8 acts with RAB23 in a membrane-tethered ubiquitination complex to regulate Hedgehog pathway transducer Smoothened, calibrating morphogen signalling strength during left–right axis specification. Disruption of MEGF8 leads to defective hedgehog and nodal signalling, underlying both craniofacial and cardiac laterality anomalies.

Integration of genetic and experimental data yields a Strong clinical validity classification. Genetic evidence includes 15 probands with biallelic MEGF8 variants and a diverse variant spectrum meeting the genetic cap. Functional evidence is Moderate given robust zebrafish rescue assays and concordant mouse models.

Key Take-home: MEGF8 should be included in diagnostic gene panels for Carpenter syndrome and heterotaxy, as hypomorphic biallelic variants reliably predict a subtype with defective lateralization.

References

• American journal of human genetics • 2012 • Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. PMID:23063620
• American Journal of Human Genetics • 2023 • Phenotypic expansion of MEGF8-associated Carpenter syndrome PMID:38760421
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy. PMID:19218456

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