FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice

Abstract

Polydactyly is a common congenital anomaly of the hand and foot. Postaxial polydactyly (PAP) is characterized by one or more posterior or postaxial digits. In a Pakistani family with autosomal recessive nonsyndromic postaxial polydactyly type A (PAPA), we performed genomewide genotyping, linkage analysis, and exome and Sanger sequencing. Exome sequencing revealed a homozygous nonsense variant (c.478C>T, p.[Arg160*]) in the FAM92A gene within the mapped region on 8q21.13-q24.12 that segregated with the PAPA phenotype. We found that FAM92A is expressed in the developing mouse limb and E11.5 limb bud including the progress zone and the apical ectodermal ridge, where it strongly localizes at the cilia level, suggesting an important role in limb patterning. The identified variant leads to a loss of the FAM92A/Chibby1 complex that is crucial for ciliogenesis and impairs the recruitment and the colocalization of FAM92A with Chibby1 at the base of the cilia. In addition, we show that Fam92a−/− homozygous mice also exhibit an abnormal digit morphology, including metatarsal osteomas and polysyndactyly, in addition to distinct abnormalities on the deltoid tuberosity of their humeri. In conclusion, we present a new nonsyndromic PAPA ciliopathy due to a loss-of-function variant in FAM92A.

Heterozygous pathogenic variants inGLI1are a common finding in isolated postaxial polydactyly A/B

“…However, despite the elevated frequency of the condition, until now only specific variants in GLI3 have been associated with dominantly inherited nonsyndromic PAP (Radhakrishna, Wild, Grzeschik, & Antonarakis, ). Autosomal recessive cases of isolated PAP have also been described, and a handful of these cases were reported with causative variants in ZNF141 , IQCE , FAM92A , and KIAA0825 (Kalsoom et al, ; Schrauwen et al, ; Ullah et al, ; Umair et al, ).…”

A novel homozygous sequence variant in GLI1 underlies first case of autosomal recessive pre‐axial polydactyly

“…Based on the location of an extra digit, polydactyly is subdivided into three types including post‐axial, mesoaxial, and pre‐axial polydactyly . Genetically, five genes including ZNF141 , IQCE , ZRS/SHH , GLI1 , GLI3 , FAM92A , and three other loci mapped on chromosome 13q21‐32, 13q13.3‐21.2, and 19p13.1‐13.2 have been associated with nonsyndromic form of post‐axial polydactyly . Clinically, pre‐axial polydactyly is featured by duplication of thumb.…”

Whole‐exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb

“…[8][9][10] In addition, variants inactivating GLI1 causing overlapping Ellis-Van Creveld syndrome and post-axial polydactyly (PAP) have been reported as well. [8][9][10] In addition, variants inactivating GLI1 causing overlapping Ellis-Van Creveld syndrome and post-axial polydactyly (PAP) have been reported as well.…”

“…Recently, three genes including ZNF141 causing PAP type A6, IQCE causing PAP type A7 and FAM92A causing PAPA have been reported. [8][9][10] In addition, variants inactivating GLI1 causing overlapping Ellis-Van Creveld syndrome and post-axial polydactyly (PAP) have been reported as well. 11 In the present study, we have investigated two families segregating non-syndromic PPD in autosomal recessive manner.…”

“…Recently, three genes including ZNF141 causing PAP type A6, IQCE causing PAP type A7 and FAM92A causing PAPA have been reported . In addition, variants inactivating GLI1 causing overlapping Ellis‐Van Creveld syndrome and post‐axial polydactyly (PAP) have been reported as well …”