Undiagnosed metabolic disorders
Gene: HMBSEnsemblGeneIds (GRCh38): ENSG00000256269
EnsemblGeneIds (GRCh37): ENSG00000256269
OMIM: 609806, Gene2Phenotype
HMBS is in 13 panels
2 reviews
Sharon Whatley (International Porphyria Network)
Relevant metabolic investigation: urine porphobilinogen
PMID: 38940544 Aasand The acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
In a patient with symptoms consistent with a porphyria disorder, the definitive diagnosis depends on the demonstration of increased accumulation and excretion of porphyrins and porphyrin precursors during an acute attack. If a patient is no longer symptomatic it may be difficult to diagnose an acute porphyria.
PMID: 27539938 Chen reports that pathogenic HMBS allele frequency is high in the general population (1/1,782) and that the HMBS gene has very low penetrance (<1%) so that genetic testing alone may be misleading and cause misdiagnosis.
PMID: 14262853 De Villeneuve, 1577472 Llewellyn, 15534187 Solis, 14970743 Hessels, 27558376 Kevelam, 31153822 Dixon and 34089223 Stutterd, reported biallelic variants in the HMBS gene in six children (5 families) with severe progressive neurological disease and in six adults (3 families) with leukoencephalopathy. A biallelic finding may lead to diagnosis in these very rare patients.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.Created: 4 Apr 2025, 3:46 p.m. | Last Modified: 4 Apr 2025, 3:46 p.m.
Panel Version: 1.627
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
176000; 620711; 620704
Publications
Rebecca Foulger (Genomics England curator)
HMBS is the third enzyme of the biosynthetic pathway leading to the production of heme. >3 unrelated cases from multiple populations providing gene:disease association. Plus animal model.Created: 23 Feb 2017, 5:14 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Porphyria, acute intermittent, 176000; Porphyria, acute intermittent, nonerythroid variant, 176000
Publications
Details
- Mode of Inheritance
- MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
- Sources
-
- Expert Review Green
- Literature
- Phenotypes
-
- Acute intermittent porphyria (Acute neuropathic porphyrias)
- Porphyria, acute intermittent, 176000
- Porphyria, acute intermittent, nonerythroid variant, 176000
- OMIM
- 609806
- Clinvar variants
- Variants in HMBS
- Penetrance
- Complete
- Publications
- Panels with this gene
-
- Inherited white matter disorders
- Hereditary neuropathy or pain disorder
- Undiagnosed metabolic disorders
- Bilateral congenital or childhood onset cataracts
- Childhood onset hereditary spastic paraplegia
- Cutaneous photosensitivity with a likely genetic cause
- Childhood onset dystonia, chorea or related movement disorder
- Likely inborn error of metabolism
- White matter disorders and cerebral calcification - narrow panel
- Hereditary neuropathy
- Acute intermittent porphyria
- Ataxia and cerebellar anomalies - narrow panel
- Non-acute porphyrias
History Filter Activity
panel promoted to version 1
Sarah Leigh (Genomics England Curator)Construction of “Undiagnosed Metabolic Disorders” (UDM) panel • The 614 genes from the neurometabolic gene panel (PMID: 27604308) added • Green genes downloaded from V1 metabolic panels (Cerebral folate deficiency, Congenital disorders of glycosylation, Hyperammonaemia, Ketotic hypoglycaemia, Mitochondrial disorders, Mucopolysaccharideosis, Gaucher, Fabry, Peroxisomal disorders), sources replaced with "Expert review green", then loaded as a review onto UDM panel, resulting in 367 green genes and 333 red (therefore 86 new green genes included from the additional metabolic panels that weren't previously on the UDM panel) • Downloaded green genes from all panels. Removed genes from none V1 panels. Removed genes from the metabolic panels mentioned above. Compared the remaining genes with the red genes from UDM panel. Loaded as an "Expert review Amber" review to the overlapping genes, (the panel name where the genes came from was used as the phenotype) • Used variant information from PMID 27604308 to review the genes on this panel • Reviewed genes on UDM panel with genes from Emory "Inherited Metabolic Disorders: Sequencing Panel" and UKGTN “Inborn Errors of Metabolism 226 panel”, changing status where appropriate, added 14 UKGTN genes that had not be listed before • Review 10 red genes that had not previously been reviewed, 4/10 were reclassified as green • Review the remaining 145 red genes that had not previously been reviewed (shared between reviewers EM, RF, LD, AT, HB, ON & SL), resulting in 60 green, 11 amber, 70 red, 4 I don’t know reviews) • Reviewed genes from PMID: 24816252 as a publication to genes found in the Inborn error or metabolism Genes metabolomics GWAS paper (figure 5). 2 new genes added
Set Mode of Inheritance, Added New Source
Ellen McDonagh (Genomics England Curator)HMBS was added to Undiagnosed metabolic disorderspanel. Source: Expert Review Green Model of inheritance for gene HMBS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added New Source
Sarah Leigh (Genomics England Curator)HMBS was added to Undiagnosed metabolic disorderspanel. Sources: Literature
Created
Sarah Leigh (Genomics England Curator)HMBS was created by sleigh