Journal Article

PUBDB-2023-08087

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants

Steel, D. B. D. ; Danti, F. R. ; Abunada, M. ; Kamien, B. ; Malhotra, S. ; Topf, M.Extern*CSSB* ; Kaliakatsos, M. ; Valentine, J. ; Nemeth, A. H. ; Jayawant, S. ; Reid, K. M. ; Mankad, K. ; Sudhakar, S. ; Ben-Pazi, H. ; Barwick, K. ; Kurian, M. A. (Corresponding author)

2023
Ovid [Erscheinungsort nicht ermittelbar]

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Please use a persistent id in citations: doi:10.1212/WNL.0000000000207241  doi:10.3204/PUBDB-2023-08087

Abstract: AbstractBackground and ObjectivesBirk-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. It has previously been reported in 2 families. We describe the clinical phenotype of 8 further individuals from 4 unrelated families with SLC30A9-related disease.MethodFollowing detailed clinical phenotyping, 1 family underwent research whole-genome sequencing (WGS), 1 research whole-exome sequencing, and 2 diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modeling, and, where relevant, sequencing of complementary DNA (cDNA) for splicing effect.ResultsIn 2 unrelated families of Pakistani origin (1 consanguineous and 1 not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included 2 affected brothers, and family 2 one affected boy. In family 3, also consanguineous, there were 4 affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was nonconsanguineous: the 1 affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5, and c.1413A>G, p.Ser471=. Despite phenotypic variability between the 4 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 modeling. Its presence in 2 unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an effect on splicing was confirmed through cDNA analysis.DiscussionPathogenic variants in SLC30A9 cause a progressive autosomal recessive neurologic 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 recognized.

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Contributing Institute(s):

1. CSSB - Leibniz-Institut für Experimentelle Virologie (LIV) / UKE - Maya Topf (CSSB-LIV/UKE-MT)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Experiment(s):

1. No specific instrument

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Database coverage:
; ; ; Allianz-Lizenz ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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