Alkuraya-Kucinskas Syndrome and Related Disorders via the BLTP1/KIAA1109 Gene

Alkuraya-Kucinskas syndrome has been reported in over ten families. Brain malformations and arthrogryposis are hallmark features (Kumar et al. 2020. PubMed ID: 32590954; Gueneau et al. 2018. PubMed ID: 29290337; Filatova et al. 2019. PubMed ID: 30485398; Guo et al. 2020. PubMed ID: 31680349). In the largest cohort study, 11 of 13 individuals presented with hydrocephaly or ventriculomegaly, 8 of 13 presented with corpus callosum agenesis, 10 of 13 presented with arthrogryposis or contractures, 12 of 13 presented with club foot, and 6 of 13 presented with heart defects (Gueneau et al. 2018. PubMed ID: 29290337). Minor features can include retrognathia, low set ears, high arched palate, webbed neck, renal defects, ophthalmoplegic defects, and neonatal breathing difficulties. Loss of function variants result in a more severe clinical presentation that is detected on a prenatal ultrasound and typically results in fetal demise or neonatal death. Individuals with bi-allelic missense variants exhibit a less severe phenotype that includes global developmental delay, mild to moderate learning disability, lack of speech, muscle hypotonia, stereotypic movements, dysmorphic features, and early-onset epilepsy. In some causes only mild intellectual disability and delayed motor milestones were noted, indicating a wide phenotypic spectrum for this disorder (Kumar et al. 2020. PubMed ID: 32590954). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in BLTP1/KIAA1109 are associated with autosomal recessive Alkuraya-Kucinskas syndrome. Reported variants include missense; nonsense; splicing; small, frameshifting deletions and duplications; and one large intragenic deletion. Loss of function variants result in a more severe phenotype, while missense variants can result in a much milder phenotype of intellectual disability and motor delays. All reported variants were inherited from a carrier parent. BLTP1 is relatively intolerant to missense variants (Genome Aggregation Database).

BLTP1 encodes a large protein (5005 amino acids) that has no known functional domains or motifs and remains functionally uncharacterized. Some studies on this gene suggest it has a possible role in embryonic development and regulation of phagocytosis (Kumar et al. 2020. PubMed ID: 32590954). The fruit fly ortholog, Tweek, is involved in synaptic vesicle recycling which may suggest a role in brain-related functions (Verstreken et al. 2009. PubMed ID: 19640479). Knockouts of the mouse or fruit fly gene orthologs result in lethality or severe neurological defects (Gueneau et al. 2018. PubMed ID: 29290337). BLTP1 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature. Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing and NGS copy number variant analysis.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the BLTP1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).