Inheritance

Autosomal dominant (with possible paternal transmission effect)

Prevalence

 1-9 / 1 000 000

Source: ORPHA:29072

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Clinical Validity Scoring Notes and points

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] describes susceptibility to pheochromocytoma and paraganglioma with autosomal dominant inheritance. The MAX gene [MIM# 154950] -MYC associated factor X- is one of the susceptibility genes resulting in genetic predisposition to PCC, mostly in patients without familial antecedents, probably due to a paternal transmission effect [PMID 21685915 and 22452945]. MAX was first reported in relation to PGL/PCC in 2011 [Comino-Méndez I et al., PMID: 21685915]. Genetic evidence includes loss of function and missense variants in MAX found in Hereditary PCC with missense variants likely being the dominant negative effect [PMID: 26070438]. Genetic evidence was scored for loss of function variants [PMID 21685915, 22452945 and 28384794]. Missense variants and deletions are also reported but not used for this curation [PMID: 26670126 and 23666964]. Experimental evidence demonstrated loss MAX gene expression and loss of heterozygosity (LOH) in patient tumors carrying LoF variants [PMID: 21685915]. Loss of functional MAX expression in a Rat Pheochromocytoma (PCC) cell line (PC12) and reduction of cell proliferation by reintroducing MAX expression [PMID: 7791753], which showed MAX is a tumor suppressor gene. Luciferase reporter activity assays with 9 missense variants confirmed the dominant negative mechanism in pathogenesis of hereditary PCC [PMID: 26070438]. The encoded MAX protein is the most conserved dimerization component of the MYC-MAX-MXD1 network of basic helix-loop-helix leucine zipper (bHLHZ) transcription factors that regulate cell proliferation, differentiation, and apoptosis. MAX is definitely associated with autosomal dominant HPGL/PCC syndrome, most commonly pheochromocytoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Clinical Validity Points Total

15.5

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023

Molecular Mechanism

Loss of function

Source: ClinGen Hereditary Cancer GCEP, accessed 07.10.2023. PMID: 21685915, 28384794.

• The ClinGen curation mentions a dominant negative effect for missense variants in PMID: 26070438. However, this paper does not appear to support a dominant negative mechanism. Summary: Transfection of PC12 cells with empty vector led to significantly higer luciferase levels than WT transfection. Transfection with a truncating variant yielded a similar effect to missense variants. To explore a dominant negative mechanism, transfected PC12 cells with wt max alone and in combo with a nonsense, and four different missense. There was no difference in luciferase levels compared to controls, suggesting that dominant negative effect does not occur for these alterations. Looking at fig S2, the results for the missense variants appear the same as the truncation, and one would expect an increased effect in the missense variants if they were acting in a dominant negative manner.

Penetrance

(list source/PMID)

Reduced (age-related with a possible parent-of-origin effect, increased risk for paternally inherited alleles)

Source: Merged Actionability Release - Clinical Genome Resources , PMID: 22452945, 21685915, 33493868

PMID: 2452945 - Sup fig S3 shows pedigree, small family sizes, but potential paternal effect can be observed.

PMID: 21685915 - table 2 shows that 3/5 families with familial antecediants had paternal antecedent. Supplementary file shows minimal evidence of this this Supp file. With one affected individual in family B, and three unaffected children of a mother in familyC.

PMID: 33493868 - one affected male individual with an affected daughter (fig 2)

PMID: 32973681 - affected female with an affected son, SUPPORTS THAT PGL-PCC DUE TO MAX IS NOT JUST PATERNALLY INHERITED.

Age of Onset

(list source/PMID)

Adulthood

Source: Merged Actionability Release - Clinical Genome Resources

Severity

Moderate

Clinical Features

• Multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma and/or a family history.

  • Paragangliomas that arise from neuroendocrine tissue, distributed from the skull base to the pelvic floor.

  • Pheochromocytomas are paragangliomas that are confined to the adrenal medulla. They typically lead to catecholemine excess.

  • Note: Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory.

• Symptoms of PGL/PCC result from effects of catecholamine hypersecretion (sustained or paroxysmal elvations in blood pressure, headach, episodic profuse sweating, forceful palpitations, pallor, and anxiety), palpable abdominal mass, enlarging mass of the skull base/neck, compromise of cranial nerves presenting as hoarseness, dysphagia, soft palate paresis, Horner syndrome; tinnitis.

Sources: PMID: 20301715

Gene SOPs & Notes

Curation Summary:

The MAX gene is associated with autosomal dominant hereditary paraganglioma and pheochromocytoma, which is characterized by increased risk of paragangliomas and pheochromocytomas that are more likely to present at younger ages, be multifocal, bilateral or recurrent and present synchronously compared to sporadic disease (PMID: 20301715). Penetrance is age related with a parent-of-origin effect, with higher risk observed in individuals with paternally inherited alleles, though maternal inheritance has been observed (PMID: 22452945, 21685915, 33493868, 32973681)

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 07.11.2023 https://broadinstitute.atlassian.net/browse/CIT-130