Submission Details

The HMBS gene was first reported in relation to acute intermittent porphyria in 1989, with the publication of four related families of Dutch ancestry (PMID: 2563167) showing autosomal dominant inheritance and incomplete penetrance (~16%). Affected individuals have since emerged from a diverse range of ethnicities, with a consistent majority of carriers remaining unaffected throughout their lifetimes. Affected individuals generally present with an acute attack of abdominal pain with nausea and vomiting, sometimes accompanied by other gastrointestinal, neurological, and/or psychiatric symptoms. Onset of such an attack typically occurs during adolescence or later, and can be triggered by barbiturate or sulfonamide drugs known to activate heme synthesis or by low caloric intake, infection, alcohol consumption, or hormones (PMID: 10343207). Among published probands, the most common phenotypes are elevated urinary levels of delta-aminolevulinic acid, porphobilinogen, and related porphyrin metabolites during an attack. Abdominal pain and vomiting during an episode can be accompanied by paralysis or other abnormalities of movement and abnormal sensations such as paresthesia, and can be followed by lasting symptoms such as chronic hypertension or renal impairment. The majority of affected individuals exhibit reduced HMBS enzymatic activity in erythrocytes, although a subset of patients do not and are characterized as having a non-erythroid form of acute intermittent porphyria that is associated with particular HMBS variants but is otherwise clinically indistinguishable. More recent studies have detected rare, severe cases of acute intermittent porphyria that harbor biallelic HMBS variants (PMID: 1577472, PMID: 15534187). These cases generally have onset in early childhood, present with additional neurological phenotypes including developmental abnormalities of the brain, ataxia, dysarthria, and seizures, and can have ocular issues such as cataracts and optic nerve hypoplasia. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (HMBS loss-of-function) was found to be consistent between the acute intermittent porphyria cases with biallelic variants and those with monoallelic variants. In addition, the phenotypic differences between the biallelic and monoallelic cases (including the non-erythroid subtype) appeared to represent a single spectrum of disease. Therefore, cases caused by inherited HMBS variants have been lumped into a single disease entity referred to as acute intermittent porphyria (MONDO:0008294, MIM #176000), with a semidominant mode of inheritance.

Nine suspected pathogenic variants have been scored as part of this curation (four missense, one single codon deletion, and four triggering splicing defects), which have been collectively reported in eleven probands in six publications (PMID: 2563167, PMID: 9860299, PMID: 15534187, PMID: 1577472, PMID: 11013452, PMID: 2789372). The mechanism of pathogenicity appears to be monoallelic or biallelic loss of HMBS function conferred by null and/or hypomorphic variants. None of the published biallelic cases harbored two alleles predicted to result in complete loss of function (PMID: 1577472, PMID: 15534187). Nine out of eleven probands were heterozygous for their respective variants, while two probands were homozygous or compound heterozygous. Five of the heterozygous probands exhibited the less common non-erythroid subtype and harbored variants disrupting the splice site of the isoform-specific intron 1 (PMID: 2563167, PMID: 9860299). Segregation evidence was available in one of these publications (PMID: 2563167) and has contributed to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature (PMID: 7757070, PMID: 2246851) but was not included in this curation as the maximum score for this category of evidence had already been reached.

This gene-disease association is also supported experimental evidence demonstrating that HMBS encodes the human enzyme responsible for catalyzing hydroxymethylbilane synthesis from porphobilinogen (PMID: 4019471, PMID: 2875434). This represents a critical step in the heme biosynthesis pathway and is consistent with the accumulation of heme precursors in the urine of affected patients. Among human tissues, the blood and spleen express the highest levels of HMBS mRNA, reflecting the relative importance of its erythroid-specific isoform (PMID: 3816774). Genetically engineered mouse and naturally occurring cat models have shown that either biallelic (PMID: 8563760, PMID: 30615115, PMID: 19934113) or monoallelic (PMID: 19934113) HMBS loss-of-function can recapitulate many of the molecular and systemic phenotypes observed in human patients, including urinary accumulation of heme precursors and neuromotor and muscular dysfunction.

In summary, HMBS is definitively associated with acute intermittent porphyria. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on May 27th, 2022 (SOP Version 9).