Compound Heterozygous Variants in a Surviving Patient With Alkuraya-Kučinskas Syndrome: A New Case Report and a Review of the Literature

Abstract

BackgroundAlkuraya–Kučinskas syndrome is an autosomal recessive disorder characterized by brain abnormalities associated with cerebral parenchymal underdevelopment, arthrogryposis, club foot, and global developmental delay. Most reported cases were cases of premature termination of pregnancies or neonatal deaths. To date, limited studies of nine surviving patients with global developmental delay and intellectual disability have been reported. In this study, we report another surviving patient.MethodsWhole-exome sequencing was utilized for the proband, and variants were filtered, annotated, and classified. Candidate variants were validated by Sanger sequencing of the proband and his family. The literature was reviewed; the prognosis among different regions and the variant type was analyzed.ResultsA non-synonymous variant [NM_015312.3: exon29: c.4892C>G (p.Pro1631Arg)] was identified and validated in the patient's father. A frameshift duplication [NM_015312.3: exon62: c.10872dupA (p.Arg3625Lysfs*5)] that caused early translation termination was identified in his mother. The literature was reviewed, variants were classified into three regions of KIAA1109, and their survival status was summarized.ConclusionWe reported another survival proband with Alkuraya–Kučinskas syndrome driven by KIAA1109. Our case expands the genotypic spectrum of Alkuraya–Kučinskas syndrome and explored the relationship between the variant region and survival.

Tweek-dependent formation of ER-PM contact sites enables astrocyte phagocytic function and remodeling of neurons

“…VPS13A mutations are linked to chorea-acanthocytosis 101,102 , VPS13B to Cohen syndrome 103 , VPS13C to Parkinson's disease with early onset [104][105][106] , and VPS13D to spastic ataxia 107 . Mutations in the human ortholog of Tweek (BLTP1) gene have been associated with Alkuraya-Kucinskas syndrome (ALKKUCS), a rare genetic condition characterized by severe intellectual disability, brain abnormalities, arthrogryposis, craniofacial and/or cardiac abnormalities 72,73,108,109 . In primary dermal fibroblasts from a single patient with ALKKUCS, disruptions in endosomal trafficking and the actin cytoskeleton were observed but the cellular and molecular basis of these phenotypes remained unclear 74 .…”