Polydactyly, also known as hyperdactyly or hexadactyly is the most common hereditary limb anomaly characterized by extra fingers or toes, with various associated morphologic phenotypes as part of a syndrome (syndromic polydactyly) or may occur as a separate event (non-syndromic polydactyly). Broadly, the non-syndromic polydactyly has been classified into three types, i.e.; preaxial polydactyly (radial), central polydactyly (axial), and postaxial polydactyly (ulnar). Mostly inherited as an autosomal dominant entity with variable penetrance and caused by defects that occur in the anterior-posterior patterning of limb development. In humans, to-date at least 10 loci and six genes causing non-syndromic polydactyly have been identified, including the ZNF141, GLI3, MIPOL1, IQCE, PITX1, and the GLI1. In the present review, clinical, genetic and molecular characterization of the polydactyly types has been presented including the recent genes and loci identified for non-syndromic polydactyly. This review provides an overview of the complex genetic mechanism underlie polydactyly and might help in genetic counseling and quick molecular diagnosis.

Polydactyly is characterized by an extra supernumerary digit/toe with or without bony element. To date variants in four genes GLI3, ZNF141, MIPOL1 and PITX1 have been implicated in developing non-syndromic form of polydactyly. The present study involved characterization of large consanguineous family of Pakistani origin segregating post-axial polydactyly type A, restricted to lower limb, in autosomal recessive pattern. DNA of two affected members in the family was subjected to exome sequencing. Sanger sequencing was then followed to validate segregation of the variants in the family members. A homozygous splice acceptor site variant (c.395-1G>A) was identified in the IQCE gene, which completely co-segregated with post-axial polydactyly phenotype within the family. The homozygous variant was absent in different public variant databases, 7000 in-house exomes, 130 exomes from unrelated Pakistani individuals and 215 ethnically matched controls. Mini-gene splicing assay was used to test effect of the variant on function of the gene. The assay revealed loss of first nucleotide of exon 6, producing a −1 frameshift and a premature stop codon 22 bases downstream of the variant (p.Gly132Valfs*22). The study provided the first evidence of involvement of the IQCE gene in limbs development in humans.

Background: Biotin–thiamine‐responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder mostly presented in children. The disorder is described as having subacute encephalopathy with confusion, dystonia, and dysarthria triggered by febrile illness that leads to neuroregression and death if untreated. Using biotin and thiamine at an early stage of the disease can lead to significant improvement.Methods: BTBGD is a treatable disease if diagnosed at an early age and has been frequently reported in Saudi population. Keeping this in mind, the current study screened 3000 Saudi newborns for the SLC19A3 gene mutations using target sequencing, aiming to determine the carrier frequency in Saudi Population and whether BTBGD is a good candidate to be included in the newborn‐screened disorders.Results: Using targeted gene sequencing, DNA from 3000 newborns Saudi was screened for the SLC19A3 gene mutations using standard methods. Screening of the SLC19A3 gene revealed a previously reported heterozygous missense mutation (c.1264A>G (p.Thr422Ala) in six unrelated newborns. No probands having homozygous pathogenic mutations were found in the studied cohort. The variant has been frequently reported previously in homozygous state in Saudi population, making it a hot spot mutation. The current study showed that the carrier frequency of SLC19A3 gene mutation is 1 of 500 in Saudi newborns.Conclusion: For the first time in the literature, we determined the carrier frequency of SLC19A3 gene mutation in Saudi population. The estimated prevalence is too rare in Saudi population (at least one in million); therefore, the data are not in favor of including such very rare disorders in newborn screening program at population level. However, a larger cohort is needed for a more accurate estimate.