Novel KIAA0825 Variants Underlie Nonsyndromic Postaxial Polydactyly

Abstract

Background: Extra digits on the hands and/or feet are a frequent condition known as polydactyly. Twelve nonsyndromic polydactyly genes have been identified, including KIAA0825.

Methods: Four consanguineous Pakistani families that segregate nonsyndromic postaxial polydactyly (PAP) with an autosomal recessive mode of inheritance were clinically and genetically evaluated. Exome sequencing or genotyping of polymorphic microsatellite markers followed by Sanger sequencing were used to identify the variants underlying the PAP etiology.

Results: Three novel KIAA0825 variants were identified that segregate with PAP: a nonsense variant c.2319G>A; p.(Trp773*) in two families; a missense variant c.970G>T; p.(Val324Phe) in one family; and a four amino acids in-frame deletion c.2743_2754del; p.(Gln915_Val918del) in one family. The nonsense variant segregated in families with PAP type B (PAPB), while the missense and the in-frame deletion variants segregated with PAP type A and B.

Conclusions: The findings of this study expanded the clinical and genetic spectrum of PAP due to KIAA0825 variants including the first KIAA0825 variant specific to PAPB.

Keywords: KIAA0825; PAP type A and type B; exome and Sanger sequencing; nonsyndromic autosomal recessive postaxial polydactyly (PAP).

Figure 1

Pedigree BD375 and clinical features for affected family members. (a) Pedigree drawing for family BD375 segregating PAPB. Squares represent males and circles females. Double lines indicate known consanguineous relationships and slash lines indicate deceased individuals. Filled symbols represent family members with PAPB and clear symbols unaffected family members. A star (*) indicates the family member whose DNA sample underwent exome sequencing. The genotype for the segregating stop gain variant c.2319G>A; p.(Trp773*) in KIAA0825 for each family member with an available DNA sample is shown below their identification number. (b) Right hand of III-3 displaying PAPB with a superfluous hanging sixth finger. (c) Left hand of III-3 with PAPB with a minute outgrowth of supernumerary sixth digit, digit clinodactyly, hand symmetry and digits identity (third, fourth, and fifth) are inarticulate. (d) Left hand of IV-8 displaying PAPB, which was the only limb displaying PAP.

Figure 2

Pedigree BD551 and clinical features for affected family members. (a) Pedigree drawing for family BD551 segregating PAPA and PAPB. Squares represent males and circles females. Double lines indicate known consanguineous relationships and slash lines indicate deceased individuals. Filled symbols represent family members with PAP and clear symbols unaffected family members. A number sign (#) indicates the family members whose DNA samples were genotyped. The genotype for the segregating missense variant [c.970G>T; p.(Val324Phe)] in KIAA0825 for each family member with an available DNA sample is shown below their identification number. (b) V-1 displays PAPA in her right hand, PAPB in left hand; and (c) PAPA in her right and left feet. (d) V-3 had PAPB in his right foot which was surgically removed and PAPA in the left foot. (e) V-3 has unaffected hands. (f) V-4 has feet displaying bilateral PAPA with dysplastic nails of the sixth toes. (g) V-4 also had bilateral PAPB of the hands, which were surgically corrected.

Figure 3

Pedigree BD650 and clinical features for affected family members. (a) Pedigree drawing for family BD650 which segregates PAPB. Squares represent males and circles females. Double lines indicate known consanguineous relationships and slash lines indicate deceased individuals. Filled symbols represent family members with PAPB and clear symbols unaffected family members. A star (*) indicates family members whose DNA samples underwent exome sequencing. The genotype for the segregating stop gain variant c.2319G>A; p.(Trp773*) in KIAA0825 for each family member with an available DNA sample is shown below their identification number. (b) V-1 has normal feet with whitish toenails. (c) Hands of V-1 with bilateral PAPB and whitish fingernails. (d) V-3 has PAPB restricted to the left hand with whitish nails. (e) Left foot of V-4 with brachydactyly and whitish nails, she had PAPB which was surgically corrected, she also has brachydactyly and whitish nails of the right foot and PAPB which was surgically corrected. (f) Left hand of V-4 with PAPB and whitish nails (g) Right hand of V-4 with PAPB and whitish nails.

Figure 4

Pedigree KA21 and clinical features for affected family members. (a) Pedigree drawing for family KA21 that segregates PAPA and PAPB. Squares represent males and circles females. Double lines indicate known consanguineous relationships and slash lines indicate deceased individuals. Filled symbols represent family members with PAP and clear symbols unaffected family members. A number sign (#) indicates the family members whose DNA samples were genotyped. The genotype for the segregating four amino acid deletion [c.2743_2754del; p.(Gln915-Val918del)] in KIAA0825 for each family member with an available DNA sample is shown below their identification number. (b) Feet of V-1 displaying bilateral PAPA originating from fifth metatarsals; (c) left hand of V-1 has unilateral PAPB with a rudimentary skin tag; (d) X-ray of the feet of V-1 displaying a fully formed extra digit with bony structure that articulates from the fifth metatarsal bone; (e) X-ray of the left hand of V-1 which does not display any additional bony structures. (f) V-2 with bilateral PAPA in both feet; (g) hands of V-2 with unilateral PAPB of the right hand; and (h) X-ray of the feet of V-2 displaying a fully formed extra digit with bony structures articulating from the fifth metatarsal.

Figure 5

All variants reported in KIAA0825 in association with PAP visualized using transcript NM_001145678.3. All variants were homozygous except the two variants with a *, which were detected as a compound heterozygous. The seven variants shown in black were previously reported. The three variants in red are the ones presented in the current study.