BDH1 – 3q29 Microduplication Syndrome

This summary evaluates the association between BDH1 (HGNC:1027) and 3q29 microduplication syndrome (MONDO_0012761) based on case report and functional evidence. Two independent clinical studies have reported copy number duplications that include BDH1. In one report, a 34‑year‑old woman with a 1.65 Mb duplication at 3q29 presented with mild intellectual disability, progressive cortical atrophy, and recurrent infections (PMID:32874693). A separate study described a family in which two affected males carried a small 3q29 microduplication involving only DGL1 and BDH1, while an unaffected sibling did not harbor the duplication (PMID:36691815). Together, these observations involve approximately 3 probands across independent families, providing a moderate level of clinical evidence.

The genetic data indicate an autosomal dominant pattern of inheritance with evidence of segregation, although the presence of an unaffected carrier suggests reduced penetrance. No individual coding variant using standard HGVS nomenclature (i.e. a c. string) was reported in these studies; rather, the association is supported by copy number variations that encompass BDH1.

In terms of genetic evidence, the reported duplications consistently overlap BDH1 and other genes, and the minimal critical region analyses implicate BDH1 as a candidate contributing to the neurodevelopmental features. Although the available data derive from only a few families, the findings are replicated across independent studies, strengthening the genetic association despite the small number of probands (PMID:32874693; PMID:36691815).

Functional assessment studies further inform the biological role of BDH1. In a murine model, knockout of Bdh1 results in significantly reduced ketone body levels and fatty liver during fasting conditions, highlighting the gene’s key role in hepatic ketogenesis (PMID:32279332). However, the biochemical consequences observed in the loss‑of‑function model do not recapitulate the neurodevelopmental phenotype seen in patients with 3q29 microduplication syndrome, indicating that the mechanistic relationship remains incompletely understood.

Integrating these clinical and experimental findings suggests a moderate overall strength for the gene‑disease association. The genetic evidence, based on duplications spanning BDH1 in affected individuals, is bolstered by segregation data and corroborated by independent case reports. Meanwhile, the functional data, although robust in demonstrating the metabolic importance of BDH1, do not fully parallel the clinical phenotype, raising the possibility of additional genetic or epistatic effects in the syndrome.

In conclusion, while the current evidence from clinical cases and animal models firmly supports a role for BDH1 in the phenotypic spectrum of 3q29 microduplication syndrome, further studies are needed to clarify the precise contribution of BDH1 dosage alterations to neurodevelopment. Key take‑home: BDH1 alterations, as evidenced by overlapping duplications in affected individuals, represent a moderate but clinically relevant factor in 3q29 microduplication syndrome, and should be considered during diagnostic evaluations.

References

• Current health sciences journal • 2020 • Phenotype Heterogeneity in 3q29 Microduplication Syndrome PMID:32874693
• Molecular genetics & genomic medicine • 2023 • 3q29 microduplication syndrome: New evidence for the refinement of the critical region PMID:36691815
• Journal of inherited metabolic disease • 2020 • Deficiency of 3‑hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting PMID:32279332

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