KIAA1109 gene mutation in surviving patients with Alkuraya-Kučinskas syndrome: a review of literature

Abstract

Background: Alkuraya-Kučinskas syndrome is an autosomal recessive disorder characterized by brain abnormalities associated with cerebral parenchymal underdevelopment, arthrogryposis, club foot and global developmental delay. KIAA1109, a functionally uncharacterized gene is identified as the molecular cause for Alkuraya-Kučinskas syndrome. Most of the reported mutations in KIAA1109 gene result in premature termination of pregnancies or neonatal deaths while a few mutations have been reported in surviving patients with global developmental delay and intellectual disability. To our knowledge, only three surviving patients from two families have been reported with missense variants in KIAA1109. In this study, we describe four surviving patients from two related families (a multiplex family) with global developmental delay and mild to severe intellectual disability with no other systemic manifestations. There were no miscarriages or neonatal deaths reported in these families.

Methods: X-chromosome exome panel sequencing was carried out in one patient and whole exome sequencing was carried out on the remaining three affected individuals and the unaffected father of the index family. Data analysis was carried out followed by variant filtering and segregation analysis. Sanger sequencing was carried out to validate the segregation of mutation in all four affected siblings and unaffected parents from both families.

Results: A novel homozygous missense mutation in a conserved region of KIAA1109 protein was identified. Sanger sequencing confirmed the segregation of mutation in both families in an autosomal recessive fashion.

Conclusion: Our study is the second study reporting a KIAA1109 variant in surviving patients with Alkuraya-Kučinskas syndrome. Our study expands the spectrum of phenotypic features and mutations associated with Alkuraya-Kučinskas syndrome.

Keywords: Arthrogryposis; Club foot; Developmental delay; KIAA clones; Mental retardation; Miscarriages; Neonatal death; Premature termination of pregnancy; Prenatal diagnosis.

Fig. 1

Pedigree and clinical photographs. a Pedigree depicting affected and unaffected individuals and consanguinity, b Clinical photographs describing dysmorphic features, simian crease and low muscle mass in legs of patient F2.IV-2 and F1.IV-2

Fig. 2

Sanger validation of KIAA1109 mutation in patients and their parents. Figure depicting chromatogram, and sequence alignments of Sanger results of KIAA1109 mutation g.123140678A > G of a F2.IV-2 and his parents and b patients F1.IV-1, F1.IV-2 and F1.IV-2 and their parents (index family). The mutated nucleotides are shown by red arrow (in chromatogram) or marked red (in sequence alignment). Sequence alignments are shown for both forward and reverse strands sequences to depict the homozygosity (in patients) or heterozygosity (in parents). Reverse strand sequences were reverse complemented before alignment

Fig. 3

Conservation analysis and protein altering mutations of KIAA1109. a conservation analysis showing the conservation of p.Thre811Ala mutation of KIAA1109 identified in this study across species. b Depiction of known mutations and novel mutation identified in this study causing Alkuraya-Kucinskas syndrome. Mutations shown in red are the mutations in surviving patients and those shown in black are the mutations identified in patients with fetal demises and neonatal deaths