SCLT1 – Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS; MONDO:0015229) is a pleiotropic autosomal recessive ciliopathy characterized by rod-cone dystrophy, truncal obesity, intellectual disability, hypogonadism, renal and hepatic dysfunction. SCLT1 (HGNC:26406) encodes a distal appendage protein essential for cilium formation. Initial evidence arose from a 22-year-old male with hepatic fibrosis, microvesicular steatohepatitis, retinitis pigmentosa, renal failure, obesity, intellectual disability and hypogonadism, in whom skipping of exons 14 and 17 in SCLT1 was detected (PMID:33132306).

In two unrelated Japanese patients clinically diagnosed with BBS, compound heterozygous SCLT1 variants c.1218G>A (exon 14 skipping) and c.1631A>G (p.Lys544Arg) were identified by NGS with confirmatory cDNA analysis (PMID:32253632). Both probands presented with early-onset rod-cone dystrophy, truncal obesity, mild intellectual disability, short stature, renal insufficiency and, in one case, hypogonadism. Parental testing confirmed trans segregation of each allele without additional affected relatives.

Functional studies demonstrate that splice site and frameshift variants in SCLT1 lead to exon skipping and premature truncation, resulting in loss‐of‐function (PMID:30425282). Immunohistochemical localization of Sclt1 to the photoreceptor basal body distal appendage corroborates a ciliary defect mechanism. Exome sequencing in inherited retinal dystrophy cohorts further revealed multiple private LoF and splice variants in SCLT1, suggesting allelic heterogeneity (PMID:28005958).

Collectively, these data support a loss-of-function mechanism for SCLT1 in BBS. The genetic evidence includes three unrelated probands with fully segregating compound heterozygous variants, and no observed non-segregation. Experimental evidence from transcript analyses and ciliary localization studies is concordant with human phenotypes.

Key Take-home: Autosomal recessive loss-of-function variants in SCLT1 cause Bardet-Biedl syndrome, underpinning clinical utility of genetic testing and informing diagnosis and management of ciliopathies.

References

• Internal Medicine (Tokyo, Japan) • 2020 • Bardet-Biedl Syndrome Caused by Skipping of SCLT1 Complicated by Microvesicular Steatohepatitis. PMID:33132306
• CEN Case Reports • 2020 • Bardet-Biedl syndrome in two unrelated patients with identical compound heterozygous SCLT1 mutations. PMID:32253632
• Scientific Reports • 2018 • Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome PMID:30425282
• PLoS One • 2016 • Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing. PMID:28005958

Evidence Based Scoring (AI generated)