Germline FH mutations presenting with pheochromocytoma.

CONTEXT: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported. OBJECTIVE AND DESIGN: To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL. RESULTS: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive. CONCLUSIONS: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.

Acrocallosal syndrome: identification of a novel KIF7 mutation and evidence for oligogenic inheritance.

OBJECTIVE: Acrocallosal syndrome (ACLS) is a rare genetically heterogeneous disorder characterised by a variety of developmental anomalies including agenesis or hypoplasia of the corpus callosum. ACLS and the related disorder, hydrolethalus syndrome, have recently been reported to be caused by mutations in the KIF7 gene. In the present study we report a 15 year follow up of a consanguineous family with ACLS and the results of exome sequencing. RESULTS: A novel in-frame deletion KIF7 mutation (p.218-221del) was detected. This is the first deletion mutation in KIF7 described in ACLS and is predicted to disrupt the KIF7 protein within the kinesin motor domain. Also present, in addition to the homozygous KIF7 mutation, were loss of function variants in known ciliopathy genes; AHI1 (p.R830W), BBS2 (p.N70S) and BBS4 (p.M472V). CONCLUSION: KIF7 has previously been demonstrated to regulate function of primary cilia and ACLS is now categorised as a ciliopathy - a group of disorders in which oligogenic disease is frequent. The finding of known loss of function variants in ciliopathy associated genes, AHI1, BBS2 and BBS4 in addition to KIF7 mutations provides evidence for oligogenic inheritance in ACLS and suggests that this might contribute to the phenotypic variability of KIF7-related disorders.