SLC29A3

Inheritance Pattern: AR

Disease ID:MONDO:0011273

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011273

Submitter: ClinGen

*SLC29A3* was first reported in relation to autosomal recessive H syndrome in 2008 (Molho-Pessach V et al., PMID: 18940313). *SLC29A3* encodes an equilibrative nucleoside transporter that mediates transport of nucleosides across lysosomal and mitochondrial membranes, and is also present in endosomes (PMID: 39412751). Among patients with H syndrome, deficient *SLC29A3* function results in impaired nucleoside export from lysosomes and lysosomal accumulation of nucleosides (PMID: 22174130), which leads to histiocytic infiltration of numerous organs. This accumulation causes disease manifestations including cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, hyperglycemia, low height, and hallux valgus and other joint contractures (as reviewed in PMID: 29527032). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: H syndrome, pigmented hypertrichosis with insulin dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis (FHC), familial sinus histiocytosis with massive lymphadenopathy (FSHML), and some forms of dysosteosclerosis. Due to overlapping symptoms, these conditions are now all lumped together as "H syndrome". Fifteen variants (8 missense, 3 frameshift, 2 nonsense, canonical 2 splice site) that have been reported in 22 probands in 7 publications (PMIDs: 18940313, 20140240, 19336477, 19889517, 22875837, 22653152, 22238637) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by the biochemical function of the gene product being consistent with the clinical and biochemical findings identified in individuals with H syndrome (PMID: 22174130), functional alteration in patient cells showing accumulation of *SLC29A3* protein (PMID: 19336477), expression in patient cells was significantly decreased compared to healthy controls (PMID: 19336477), and animal models that recapitulate the human phenotype (PMIDs: 31270333, 19336477). In summary, there is definitive evidence supporting the relationship between *SLC29A3* and autosomal recessive H syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on May 7, 2024 (SOP Version 10). **Addendum from the Monogenic Diabetes GCEP**: Variants in SLC29A3 were first reported in association with diabetes in the form of pigmented hypertrichosis with insulin dependent diabetes mellitus (PHID) syndrome in 2009 based on a homozygosity mapping study in six individuals in five unrelated families. Homozygosity for two truncation variants and five missense variants was identified (PMID:19336477). The mechanism for diabetes appears to be related to beta cell loss due to apoptosis induced by the loss of the *SLC29A3* gene product human equilibrative nucleoside transporter 3 (hENT3) (PMID:26163994). The diabetes in PHID was originally described as predominantly antibody-negative (PMIDs:19175903,17461801). However, a recent case series reported that 4 out of 7 patients, all diagnosed between the ages of 3 and 14 with PHID, had at least one positive antibody (PMID:38163427). Therefore, the presence of autoantibodies should thus not preclude testing for PHID in children with diabetes in the presence of consanguinity along with features of PHID including dysmorphic facial features, characteristic skin lesions, hematological abnormalities, and developmental delay (PMID:38163427). Individuals presenting with diabetes and found to have PHID through genetic testing are recommended to undergo early hearing and vision screening to improve neurocognitive outcomes and to be referred to a specialized dermatologist for skin lesions to prevent joint contractures (PMID:38163427). Individuals presenting with features of SLC29A3-related disorders (H syndrome) and found to have biallelic pathogenic *SLC29A3* variants should undergo glycemic screening to enable early treatment for diabetes. This amendment was approved by the ClinGen Monogenic Diabetes GCEP on April 30, 2025.

Inheritance Pattern: AR

Disease ID:MONDO:0009138

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011273

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011273

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0011273

Submitter: PanelApp Australia