Paragangliomas 7

A number sign (#) is used with this entry because of evidence that paragangliomas-7 (PGL7) is caused by heterozygous mutation in the DLST gene (126063) on chromosome 14q24.

Description

Paragangliomas-7 (PGL7) is an autosomal dominant tumor predisposition syndrome in which affected individuals develop adult-onset neuroendocrine neoplasms, know as paragangliomas. Most tumors arise in the abdomen, secrete normetanephrine, and follow a benign disease course (summary by Remacha et al., 2019).

For a phenotypic description and a discussion of genetic heterogeneity of familial paragangliomas, see PGL1 (168000).

Clinical Features

Remacha et al. (2019) reported 4 unrelated patients who developed multiple thoracic abdominal normetanephrine-secreting PGLs between 24 and 38 years of age. One patient also developed a pheochromocytoma and another developed a uterine endometrioid carcinoma. All tumors were benign. None of the patients had a family history of the disorder.

Inheritance

The transmission pattern of PGL7 in the families reported by Remacha et al. (2019) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In 4 unrelated patients (patients 3-6) with PGL7, Remacha et al. (2019) identified the same germline heterozygous missense mutation in the DLST gene (G374E; 126063.0001). Analysis of tumor tissue available from 3 of the patients showed loss of heterozygosity (LOH) for DLST due to uniparental disomy (UPD) of the paternal chromosome. None of the patients had a family history of the disorder, although 3 probands had asymptomatic family members who carried the mutation, consistent with incomplete penetrance; the pedigree in 1 patient suggested de novo occurrence. Knockdown of the DLST gene in human H838 cells resulted in a significant block in carbon flow in the tricarboxylic acid (TCA) cycle, and this defect could be rescued by wildtype DLST, but not by the G374E mutant. In vitro functional expression studies showed that the G374E mutant had compromised catalytic activity compared to wildtype, resulting in a high alpha-KG/fumarate ratio and accumulation of the oncometabolite 2-hydroxyglutaric acid (2HG), particularly the L-2HG enantiomer. Analysis of patient tumors showed strong immunostaining for DLST as well as a hypermethylated phenotype, categorized in the non-CIMP (CpG island methylator phenotype) cluster, and a pseudohypoxic state with increased expression of HIF3A (609976). The findings indicated that DLST can act as a tumor suppression gene and highlighted abnormalities in the TCA cycle as playing a role in the pathogenesis of paragangliomas. The mutation, which was found by targeted next-generation sequencing of candidate TCA genes among 104 unrelated patients with PGL, was confirmed by Sanger sequencing. Heterozygous missense variants in DLST (R231Q, D304N, and Y422C) were found in 3 additional probands, but in vitro functional studies of these 3 other missense variants indicated that they behaved similar to wildtype DLST in the assay used. Another patient carried a heterozygous splice site mutation, but this was not further studied. None of the patients besides those with the G374E variant showed LOH in tumor tissue. However, Remacha et al. (2019) could not exclude that these variants had other unknown effects.