Submission Details

SLC16A2 was first reported in relation to X-linked Allan-Herndon-Dudley syndrome in 2004 (Dumitrescu et al., PMID: 14661163). Affected males show high serum 3,3',5-triiodothyronine (T3) concentration and low serum 3,3',5'-triiodothyronine (reverse T3) concentration, along with severe intellectual disability, infantile hypotonia, progressive spastic quadriplegia, and joint contractures. While heterozygous female carriers do not manifest psychomotor abnormalities, they have intermediate thyroid test abnormalities between affected and normal individuals.

Eleven variants (missense, nonsense, frameshift), either familial or de novo, that have been reported in 11 probands in six publications (PMIDs: 14661163, 15488219, 15889350, 17899191, 19194886, 20713192) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. To date, 33 unique variants within SLC16A2 have been classified as pathogenic in ClinVar. This gene-disease relationship is also supported by patient-derived neural cells and a chicken model, although mouse models do not show apparent neurological phenotypes (not curated here).

In summary, there is definitive evidence supporting the relationship between SLC16A and X-linked Allan-Herndon-Dudley 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 Intellectual Disability and Autism Gene Curation Expert Panel on August 9, 2018 (SOP Version 5).

The SLC16A2 gene has been associated with X-linked Allan-Herndon-Dudley syndrome using the ClinGen Clinical Validity Framework as of 8/8/2018. The affected males show high serum 3,3',5-triiodothyronine (T3 ) concentration and low serum 3,3',5'-triiodothyronine (reverse T3 or rT3) concentration, along with other phenotypes: severe cognitive deficiency, infantile hypotonia, progressive spastic quadriplegia, and joint contractures. While heterozygous female carriers do not manifest psychomotor abnormalities, they have intermediate thyroid test abnormalities between affected and normal individuals. This disease association was made using case-level data and experimental data. At least 11 variants (missense, nonsense, frameshift), either familial or de novo, were curated from six publications (PMID: 20713192, 14661163, 15488219, 17899191, 15889350, and 19194886). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The disease association was first reported in human as early as 2004 (Dumitrescu et al., 2004 PMID: 14661163). To date, 33 unique variants within SLC16A2 have been classified as Pathogenic in ClinVar. This gene-disease association is supported by animal model (chicken) and patient-derived neural cells, although mouse models do not show apparent neurological phenotype (not curated here). In summary, SLC16A2 is definitively associated with X-linked Allan-Herndon-Dudley syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

According to the curation SOP, the segregation score should downgrade from 3.0 to 1.5, because all of the LOD scores calculated in this curation are based on candidate gene sequencing instead of exome/genome or all genes sequenced in the linkage regions. SLC16A2 encodes for two potential proteins, 613 and 539 amino acids, due to two alternative start sites on exon 1, although NCBI Gene only lists the one with 539 amino acids (NM_006517.4). All of the variants described in this curation is based on NM_006517.4, therefore some of the variants may seem different from the original study.