ClinGen Dosage Sensitivity Curation Page

SLC35A2

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
27743886 2-month old girl had refractory epileptic spasms with hypsarrhythmia. She had developmental delay, widely spaced inverted nipples, external strabismus, and bilateral heterochromia of irises. MRI revealed cerebral and cerebellar atrophy, thinning of the corpus callosum, and arachnoid pouch. Whole-exome sequencing detected a de novo frameshift mutation c.950delG (p.Gly317Alafs*32) at exon 4 in SLC35A2. Seizures resolved by 3 years of age but she had intellectual disability.
24115232 In a cohort of 328 patients with early infantile epileptic encephalopathy, authors identified de novo frameshift mutations in SLC35A2 in two female patients: c.433_434del (p.Tyr145Profs*76) in patient 1 and c.972del (p.Phe324Leufs*25) in patient 2. A third female patient had a de novo missense mutation (c.638C>T [p.Ser213Phe]). X-inactivation analysis using a fragile X mental retardation locus methylation assay and human androgen receptor assay on genomic DNA from peripheral leukocytes showed a markedly skewed patternin patients 1 and 2 and was not informative in patient 3.
23561849 This report two male individuals with de novo mosaic mutations in SLC35A2 (p.Gly8Serfs?9 and p.Val331Ile). A female with a de novo predicted loss-of-function mutation was also identified (p.Met1?). Three three patients showed an unusual transferrin profile, with loss of both galactose and sialic acid from multiple branches of complex type N-glycans. Functional analysis with fibroblast lines confirmed incomplete galactosylation, which leads to incomplete sialylation. By three years of age, the transferrin profile seems to revert to normal, despite worsening of the phenotype.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.