Biallelic variants in SLC35B2 cause a novel chondrodysplasia with hypomyelinating leukodystrophy

Abstract

Sulfated proteoglycans are essential in skeletal and brain development. Recently, pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis have been identified in a range of chondrodysplasia associated with intellectual disability. Nevertheless, several patients remain with unidentified molecular basis. This study aimed to contribute to the deciphering of new molecular bases in patients with chondrodysplasia and neuro-developmental disease. Exome sequencing was performed to identify pathogenic variants in patients presenting with chondrodysplasia and intellectual disability. The pathogenic effects of the potentially causative variants were analyzed by functional studies. We identified homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2 in two patients with pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy. By functional analyses, we showed that the variants affect SLC35B2 mRNA expression and protein subcellular localization leading to a functional impairment of the protein. Consistent with those results, we detected proteoglycan sulfation impairment in SLC35B2 patient fibroblasts and serum. Our data support that SLC35B2 functional impairment causes a novel syndromic chondrodysplasia with hypomyelinating leukodystrophy, most likely through a proteoglycan sulfation defect. This is the first time that SLC35B2 variants are associated with bone and brain development in human.

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

“…Therefore, variants in 15/135 cases (11.11%) would have not been detected by using. Of those 15 missed cases, 6 cases carried variants in our recently validated candidate genes in 2020 (SHMT2 [39], 2021 (DLG4 [42], 2022 (SLC35B2 [45] and publications on progress, explaining absence of these genes from panels. The other 9 missed cases are related to atypical phenotypes or non-classical HSP genes (L2HGDH, NDUFS6, SARS1 [49], KMT2B, TRMT5, COL6A3, LONP1, MMUT and PDK3).…”

“…This approach allowed us to identify 14 novel candidate genes, for which we gathered additional international cases with compatible phenotypes through the platform GeneMatcher [44]. We functionally validated and reported seven novel disease-causing genes (SHMT2 [39], UBAP1 [41], PI4KA [38], PCYT2 [40], SLC35B2 [45], SVBP (Launay et al, under review), and DLG4 [42]) (Table 2), with three additional novel disease genes undergoing functional characterization, confirmed through three or more international additional families via GeneMatcher. Four more candidate genes are awaiting confirmation through the analysis of additional patients, while functional studies are ongoing.…”

“…Among the 95 cases diagnosed, 56 harboured biallelic variants (34 homozygous variants; 16 of them in reported consanguineous families), 36 showed an autosomal-dominant mode of inheritance (11 de novo) and 3 cases were caused by mutation in an X-linked gene. Moreover, we identified two uniparental disomy events of maternal origin: one event was observed on chromosome 16 in patient IDSPG10, who harboured a nonsynonymous single-nucleotide variant in the FA2H gene [50,51]; the other event occurred on chromosome 6 in patient IDLNF68 with a frameshift deletion variant in the SLC35B2 gene [45]. Segregation by Sanger sequencing was performed in all but 10 patients due to the unavailability of parental samples.…”

Emerging cellular themes in leukodystrophies

“…Homozygous mutations in SLC35B2 were found in two patients presenting with chondrodysplasia (disrupted growth of cartilage), intellectual disability, and hypomyelination on brain MRI ( Guasto et al, 2022 ). The SLC35B2 gene (also known as PAPST1 ) encodes a 3′-phosphoadenosine 5′-phosphosulfate (PAPS) transporter that moves PAPS from the cytoplasm into the Golgi apparatus.…”

“…This process generates sulfated proteoglycans (PGs), which are important in the extracellular matrix for building and maintaining connective tissues in bones, cartilage, and even brains ( Schwartz and Domowicz, 2018 ). Biochemical analyses of sulfated proteins in both patient fibroblasts and serum indicate reductions in protein sulfation ( Guasto et al, 2022 ). Moreover, in a transfected kidney cell line, mutant SLC35B2 lost its Golgi-specific localization and instead appeared throughout the cell.…”