Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

Abstract

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.

Fig. 1

A Pedigree drawing of family BD204 segregating autosomal recessive postaxial polydactyly type A and B. Males are denoted by squares while females are display as circles. Family members affected with PAP are denoted by a filled in symbol and unaffected members by a clear one. Consanguineous unions are delineated by double lines. A diagonal line through a square or circle represents a deceased family member. DNA samples were obtained from individuals for which a genotype is shown. A star (*) indicates availability of exome sequence data. B Photographs and radiographs for affected members of family BD204. Individual V:1 displays PAP-A of both feet (a) and hands exhibiting an extra digit articulated with the fifth metacarpal along with mild clinodactyly in the fifth digit of both hands (b, c). For individual V:2, the right and left foot present with PAP-A (d, e), and the right hand presents with PAP-B that is characterized by a rudimentary tissue tag, extending from fifth finger (f). The left hand of V:2 presents with PAP-A, displaying a sixth finger outspread from the fifth metacarpal (g). V:2 also presents with mild along with mild clinodactyly in the fifth digit of both hands (f, g). Radiographic features of the feet of patient (V:2) reveal a diphalangeal extra digit articulated with fifth metatarsal in the right foot (h). A diphalangeal extra digit and a bifurcated and broad metatarsal is visible in the left foot (i). Radiographs of hands of affected individual (V:2) show PAP-A in left hand (k). The extra finger occurs in the form of a discrete digit having two phalanges (k). Bony abnormalities can be excluded in the right hand (j)

Fig. 2

A Pedigree drawing of family PD-23 segregating autosomal recessive postaxial polydactyly type A. Family members affected with PAP are denoted by a filled in symbol and unaffected members by a clear one. Consanguineous unions are delineated by double lines. A diagonal line through a square or circle represents a deceased family member. DNA samples were obtained from individuals for which a genotype is shown. A star (*) indicates availability of exome sequence data. B Photographs and radiographs for family PD-23. Individual IV:2 displays PAP-A of both feet (a) and hands (b). For individual VI:1 the left foot displays postaxial hexadactyly with a well-developed diphalangeal additional toe while the right foot is clinically and radiologically normal (c, e). The hands of individual VI:1 do not show any clinical or radiological abnormality (d, f). Individual VI:5 displays unilateral PAP-A of the left hand with an extra digit arising from the fifth metacarpal, mild camptodactyly in the fifth digit of both hands. as well as PAP-A of the right foot (g, h)

Fig. 3

Heatmap representation of RNA-seq data queried from ENCODE of polydactyly genes in the developing mouse limb from E11.5 through E15.5. The 2210408IRik gene, the closest mouse KIAA0825 ortholog, has a steady expression level in the developing limb. Here, it is plotted together with other non- syndromic i.e., Zfp941 (ZNF141 ortholog), Iqce, Gli3 and syndromic polydactyly genes i.e., Bbs1, Mks1. TPM transcripts per kilobase million