Addressing diagnostic gaps and priorities of the global rare diseases community: Recommendations from the IRDiRC diagnostics scientific committee.

The International Rare Diseases Research Consortium (IRDiRC) Diagnostic Scientific Committee (DSC) is charged with discussion and contribution to progress on diagnostic aspects of the IRDiRC core mission. Specifically, IRDiRC goals include timely diagnosis, use of globally coordinated diagnostic pipelines, and assessing the impact of rare diseases on affected individuals. As part of this mission, the DSC endeavored to create a list of research priorities to achieve these goals. We present a discussion of those priorities along with aspects of current, global rare disease needs and opportunities that support our prioritization. In support of this discussion, we also provide clinical vignettes illustrating real-world examples of diagnostic challenges.

Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.