ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Additional Literature Review: In addition to the Iberian founder mutation, a Dutch founder deletion has also been described, involving exon 3 (c.201-4429_287-933del) (PMID: 25827221). A deletion of exons 1 and 2 has also been reported in an individual of Japanese descent (PMID:20379037). PMID: 29386252 Andrews et al (2017) performed a retrospective survey of 1832 individuals with personal or family history of pheochromocytoma/paraganglioma. A total of 673 had germline SDHB variants detected, of which 36 had single or multi-exon deletions and duplications. The most common copy number variants were exon 1 deletion (n=18, 49%), exon 3 deletion (n=5, 14%) and whole gene deletion (n=2, 5.6%). No whole gene duplications were identified. PMID: 27485256 Hoekstra et al (2016) utilized MLPA analysis and breakpoint mapping of index patients with paraganglioma/pheochromocytoma who had tested negative for SDH gene sequence variants to identify 7 unique intragenic deletions within SDHB in 8 cases (no other genes involved). Two cases with whole gene deletion were also detected (contiguous multi-gene deletion confirmed for one, other unknown). Inheritance was not assessed. PMID: 19454582 Burnichon et al (2009) tested a cohort of 445 patients with paragangliomas. Germline SHDB variants were identified in 96 patients, of which four unique large deletions, 12 frameshift, 7 splice site, 12 nonsense and 23 missense. Of the large deletions, one was the ~20kb deletion described by Cascon et al. PMID: 12618761 Benn et al (2003) identified novel SDHB variants in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. PMID:19351833 A patient with paraganglioma in Neumann et al (2009) showed an exon 3 duplication, but there are no reports of whole gene duplication. Note on Penetrance of SDHB variants: PMID: 26113606 Baysal and Maher (2015) note that for "germline SDHB mutations, the increased use of presymptomatic genetic testing in extended families has resulted in recognition that the penetrance of SDHB mutations is lower than initially thought. Thus initial estimates of the penetrance of germline SDHB mutations were in excess of 70% but have progressively fallen to 25?40% (Benn et al. 2006, Solis et al. 2009, Hes et al. 2010, Ricketts et al. 2010, Schiavi et al. 2010)."

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity