SLC35D1 – Schneckenbecken Dysplasia

SLC35D1 encodes a UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter localized to the endoplasmic reticulum membrane. Pathogenic variants in SLC35D1 cause Schneckenbecken dysplasia, a rare lethal skeletal dysplasia characterized by a snail-like pelvis, flattened vertebral bodies, broad long bones with dumbbell appearances, and thoracic hypoplasia. Affected individuals present with short stature, genu valgum, and narrow chest on clinical examination.

Initial genetic studies identified loss-of-function SLC35D1 mutations in five families (PMID:19508970), including nonsense, splice-site, frameshift, and missense variants c.319C>T (p.Arg107Ter), c.876+1G>A, c.64_70del (p.Thr22fs), c.464+1G>C, and c.193A>C (p.Thr65Pro), in six fetal cases (PMID:19508970). No SLC35D1 mutations were found in other severe spondylodysplastic dysplasias, supporting locus specificity.

A large consanguineous pedigree with eight affected individuals demonstrated homozygosity for a novel missense variant c.401C>T (p.Met134Thr) segregating with a milder Schneckenbecken dysplasia phenotype across siblings, cousins, and an uncle (PMID:35934917). Affected family members exhibited short stature, mild mesomelia, genu valgum, and narrow thorax, with ages ranging 4–31 years, indicating phenotypic variability.

Variant spectrum now spans four loss-of-function alleles, the hypomorphic p.Pro133Leu variant (PMID:31423530) causing Schneckenbecken-like dysplasia, and the p.Met134Thr allele associated with attenuated disease. All variants follow autosomal recessive inheritance and demonstrate homozygous or compound heterozygous configurations.

Functional assays confirm pathogenicity through exon trapping demonstrating exon 4 skipping (p.L109fsTer18) and yeast complementation showing loss of transporter activity for p.Thr65Pro (PMID:19508970). Biochemical transport assays reveal significantly reduced UDP-sugar transport for p.Pro133Leu (PMID:31423530), and mouse Slc35d1 knockout replicates the lethal skeletal phenotype.

Together, robust genetic and experimental data define SLC35D1-deficient Schneckenbecken dysplasia as an autosomal recessive disorder with a spectrum from lethal perinatal cases to milder, survivable phenotypes. Key take-home: SLC35D1 testing is critical for accurate prenatal and postnatal diagnosis and for guiding genetic counseling in Schneckenbecken dysplasia.

References

• Journal of medical genetics • 2009 • Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases. PMID:19508970
• American journal of medical genetics. Part A • 2022 • A novel SLC35D1 variant causing milder phenotype of Schneckenbecken dysplasia in a large pedigree. PMID:35934917
• Human molecular genetics • 2019 • A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia. PMID:31423530

Evidence Based Scoring (AI generated)