ClinGen Dosage Sensitivity Curation Page

SMS

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
14508504 Cason et al. (2003) analyzed SMS in 9 families with XLID. They found a splice site mutation (329+5 G>A) in SMS in a family with Snyder-Robinson syndrome that segregated with the affected males. This change was not detected in 480 normal males. The enzyme activity of SMS was analyzed in the affected individuals and found to be ~5% of normal controls.
18550699 de Alencastro et al. (2008) found a missense mutation (G56S) in SMS that segregated with disease in a family with a severe form of Synder-Robinson syndrome. The mutation was not detected in 448 normal males and 138 normal females. Supporting evidence that this missense mutation is pathogenic: 1) the G56 residue is highly conserved and 2) SMS enzyme activity could not be detected in 3 of the affected patients.
19206178 Becerra-Solano et al. (2009) found a missense mutation (V132G) in SMS in 2 affected brothers with Synder-Robinson syndrome, but not in their 2 normal brothers. The mutation was not detected in 549 normal X chromosomes. Supporting evidence that this missense mutation is pathogenic: 1) the V132 residue is highly conserved and 2) SMS enzyme activity was significantly reduced in the affected individuals.

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.