FZD2 – Autosomal Dominant Omodysplasia

Autosomal dominant inheritance has been established for omodysplasia (MONDO:0008123) associated with heterozygous FZD2 variants. Initially, a de novo missense variant c.1301G>T (p.Gly434Val) was identified in a single proband with hypertelorism, bilateral cleft lip/palate, microretrognathia and short upper limbs (PMID:29230162). Subsequently, two unrelated patients harboring the recurrent nonsense variant c.1644G>A (p.Trp548Ter) were reported (PMID:30455931), and familial segregation of the same c.1644G>A (p.Trp548Ter) allele was demonstrated in a two-generation kindred (PMID:25759469), confirming autosomal dominant transmission.

To date, five affected individuals across three unrelated families have been documented, including two de novo events and one instance of mother-to-daughter transmission, implicating both missense and protein-truncating variant classes. The missense change c.1301G>T (p.Gly434Val) and the nonsense change c.1644G>A (p.Trp548Ter) account for all reported alleles and recur in independent kindreds ([PMID:29230162]; [PMID:30455931]; [PMID:25759469]).

Mechanistically, the p.Trp548Ter protein exhibits reduced interaction with Dishevelled and fails to mediate canonical Wnt signaling in vitro (PMID:25759469). In vivo, a humanized Fzd2W553* knock-in mouse and two deletion alleles recapitulate cleft palate, limb shortening and perinatal lethality, which can be rescued by the DKK inhibitor IIIC3a (PMID:36789910). Craniofacial assays in chicken embryos expressing human p.Gly434Val demonstrate dominant-negative effects on chondrogenesis and SOX9 reporter activity, further impairing canonical and non-canonical Wnt pathways (PMID:38967226).

Clinically, FZD2-related omodysplasia presents with hypertelorism (HP:0000316), microretrognathia (HP:0000308), short humeri, radial head dislocation, short first metacarpals and variable clefting. Intellectual disability has been observed in one patient, suggesting an expanded phenotype (PMID:30455931).

No conflicting evidence has been reported, and all functional and genetic data are concordant. The combination of multiple de novo occurrences, segregation in a family, variant recurrence and robust in vitro and in vivo phenotypic modeling supports a Moderate clinical validity classification under ClinGen.

Key Take-home: Heterozygous FZD2 variants cause autosomal dominant omodysplasia through a dominant-negative disruption of Wnt signaling, enabling molecular diagnosis and potential therapeutic targeting.

References

• Molecular syndromology • 2017 • A Novel de novo FZD2 Mutation in a Patient with Autosomal Dominant Omodysplasia. PMID:29230162
• Clinical case reports • 2018 • Two unrelated patients with autosomal dominant omodysplasia and FRIZZLED2 mutations. PMID:30455931
• Human molecular genetics • 2015 • A mutation in FRIZZLED2 impairs Wnt signaling and causes autosomal dominant omodysplasia. PMID:25759469
• Development (Cambridge, England) • 2023 • Successful therapeutic intervention in new mouse models of frizzled 2-associated congenital malformations. PMID:36789910
• Disease models & mechanisms • 2024 • Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome. PMID:38967226

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