HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing.

Abstract The heterooctameric mitochondrial trifunctional protein (MTP), composed of four α- and β-subunits harbours three enzymes that each perform a different function in mitochondrial fatty acid β-oxidation. Pathogenic variants in the MTP genes (HADHA and HADHB) cause MTP deficiency, a rare autosomal recessive metabolic disorder characterized by phenotypic heterogeneity ranging from severe, early-onset, cardiac disease to milder, later-onset, myopathy and neuropathy. Since metabolic myopathies and neuropathies are a group of rare genetic disorders and their associated muscle symptoms may be subtle, the diagnosis is often delayed. Here we evaluated data of 161 patients with myopathy and 242 patients with neuropathy via next generation sequencing (NGS) and report the diagnostic yield in three patients of this cohort by the detection of disease-causing variants in the HADHA or HADHB gene. The mitigated phenotypes of this treatable disease were missed by the newborn screening, highlighting the importance of phenotype-based NGS analysis in patients with rare and clinically very variable disorders such as MTP deficiency. Highlights • MTP deficiency is a rare metabolic disorder characterized by phenotypic heterogeneity. • The diagnosis of MTP deficiency is often delayed. • Pathogenic variants in HADHA and HADHB cause MTP deficiency. • Phenotype-based NGS-analysis should be used to identify the cause of MTP deficiency disorders. [ABSTRACT FROM AUTHOR]