ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
16258955 Cascon et al (2006) describe germline deletions of SDHB in patients with paragangliomas. 3 individuals showed deletion, including two unrelated individuals (of Portuguese and Spanish descent, respectively) with intragenic exon 1 deletions and one individual with a whole gene deletion. These deletions were detected by multiplex PCR and confirmed by quantitative real-time PCR. For the whole gene deletion and one of the exon 1 deletions, familial studies were unable to be performed. The individual with the second exon 1 deletion, a 14 year old female with a paraganlioma, had a positive family history of paraganglioma in her father. Her father was found to have the same deletion, as were her two older brothers, who were not reported to have paraganglioma, but were noted to have high levels of dopamine in their urine. No functional assays were performed. In 2008, after identifying 3 additional individuals with exon 1 deletions (2 of Spanish and 1 of French descent), Cascon et al. (PMID: 18057081) showed that all 4 Iberian Peninsula families had the same deletion breakpoints, resulting in a 15.69-kb deletion. Haplotype analysis indicated a founder effect. The French family was found to have different breakpoints.
19389109 Solis et al (2009) describe a large Spanish-Mexican kindred with an inherited exon 1 deletion of SDHB corresponding to the 15.69 kb common deletion. 41 mutation carriers were found, with 11 individuals diagnosed with paraganglioma. 30 carriers were apparently healthy, indicating reduced penetrance of ~35% by age 40.
17652212 Amar et al (2007) describe a cohort of patients with malignant paragangliomas or pheochromocytomas and variants in SDHB, including one individual with a nonsense variant, three with deletions involving one or more exons (2 individuals had a deletion of exon 1, a single individual had a deletion of exons 3-8). No functional studies were performed. No comment was made regarding the ethnicity of the individuals with the exon 1 deletions (or whether these corresponded to the common 15.69 kb deletion identified in individuals of Spanish/Portuguese descent), though all three of the patient recruitment sites were in France.

Evidence for Triplosenstive Phenotype

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.