Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants.

Abstract

Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9 presenting with a complex movement disorder, developmental regression, oculomotor abnormalities and renal impairment. So far it has been reported in only two families. We describe the clinical phenotype of eight further individuals from four unrelated families with SLC30A9-related disease. Following detailed clinical phenotyping, one family underwent research whole-genome sequencing (WGS), one research whole-exome sequencing (WES) and two diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modelling and where relevant, sequencing of cDNA for splicing impact. In two unrelated families of Pakistani origin (one consanguineous, one not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included two affected brothers, and Family 2 one affected boy. In Family 3, also consanguineous, there were four affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was non-consanguineous: the one affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5 and c.1413A>G, p.Ser471=. Despite phenotypic variability between the four families, all affected patients manifested with a progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis. None had evidence of severe renal impairment. For the novel missense variant, the conformation of the loop domain and packing of transmembrane helices are likely to be disrupted based on structure modelling. Its presence in two unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an impact on splicing was confirmed through cDNA analysis. Pathogenic variants in SLC30A9 cause a progressive autosomal recessive neurological syndrome associated with a complex hyperkinetic movement disorder. Our report highlights the expanding disease phenotype, which can present with a wider spectrum of severity than has previously been recognised.