Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease

•Two siblings with HIBCH deficiency identified through exome sequencing•Disease incidence estimates suggest that HIBCH deficiency may be under-diagnosed.•Retrospective analysis of NBS cards found elevated 3-hydroxy-isobutyryl-carnitine•ACMG algorithms could be modified to include HIBCH deficiency for elevated C4-OH.•Acylcarnitines should be included in the work-up of patients with Leigh syndrome.

Purpose3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS).MethodsWhole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI–MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals.ResultsTwo siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C > T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients' fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~ 130,000 individuals.ConclusionWe describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient's NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.