Two unrelated patients with autosomal dominant omodysplasia and FRIZZLED2 mutations

Abstract

Key Clinical MessagePresented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical.

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

“…Interestingly, four females with FZD2 -related RS, of 11 females studied, were found to have anomalies of the uterus: BAB7987 and BAB7988 have retroverted uterus, while BAB11377 and patient 1 reported by Warren et al. 51 were found to have a bicornuate uterus.…”

“…We found sixteen (16 out of 22, 73%) of the 22 studied subjects had pathogenic or likely pathogenic variants in 4 RS-related genes ( DVL1 , DVL3 , FZD2 , and WNT5A ) or a candidate gene ( DVL2 ), including nine novel (10 individuals) and three recurrent variants (six individuals). As shown in Figure 1 , altogether, 18 unique variants from 24 unrelated subjects in DVL1 , 3 , 4 , 9 , 11 , 44 , 45 10 variants in 10 DVL3 -unrelated individuals, 3 , 11 , 46 , 47 seven variants in 14 unrelated FZD2 individuals, 3 , 48 , 49 , 50 , 51 and 11 variants in WNT5A from 12 unrelated subjects 3 , 16 , 17 , 18 , 52 were identified ( Figure 1 , Table S4 ).

Figure 1 Map location of identified variants in RS-related genes resulting in AD-RS Previously described variants (blue circles) and variants identified in this study (red circles) are shown.

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Generation of a New Frizzled 2 Flox Mouse Model to Clarify Its Role in Development

“…The Fzd2 tm1Eem flox allele [16] was reported to develop lung cysts and loss of branching in embryonic lungs in Shh-cre;Fzd2 tm1Eem homozygotes. Given the association of FZD2 mutations with the rare human syndromes Autosomal Dominant Omodysplasia [8][9][10][11] and Robinow Syndrome (RS) [12], which present with craniofacial anomalies and limb reductions, we wanted to assess the phenotypes of mice lacking Fzd2 in these tissues. Interestingly, we saw dramatic phenotypes when we heterozygously deleted Fzd2 in limb precursor cells (Prx1-cre…”

“…Our interests in Wnt signaling regulation of development and disease led us to specifically study Fzd2 due to the association of FZD2 heterozygous mutations with the human syndromes Autosomal Dominant Omodysplasia (ADO) [8][9][10][11] and Robinow Syndrome (RS) [12]. These syndromes present with limb reductions and craniofacial anomalies.…”

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

“…As mentioned, heterozygous mutations in FZD2 can cause OMOD2. To date, one missense mutation (p.Gly434Val) and two nonsense mutations involving adjacent amino acids (p.Ser547 * and p.Trp548 * ) have been reported (92)(93)(94)(95). The nonsense mutations are located in the intracellular domain of FZD2, more precisely in the conserved DVL binding motif (KTxxW).…”