Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation. Issue 1 (15th October 2021)

• Record Type: Journal Article
• Authors: Ocansey, Sharon; Pullen, Debbie; Atkinson, Patricia; Clarke, Antonia; Hadonou, Medard; Crosby, Charlene; Short, John; Lloyd, Ian Christopher; Smedley, Damian; Assunta, Albanese; Shah, Pratik; McEntagart, Meriel
• Is Part Of: Clinical dysmorphology. Volume 31:Issue 1(2022)
• Page Start: 11
• Page End: 17
• Publication Date: 2021-10-15
• Subjects: DNAJC3 -- hyperinsulinism -- hypoglycaemia -- hypothyroidism -- Neurodegeneration; Abnormalities, Human -- Periodicals; Genetic disorders -- Periodicals; Abnormalities -- periodicals; Abnormalities, Human; Periodicals; 616.042
• DOI: 10.1097/MCD.0000000000000397
• Languages: English
• ISSNs: 0962-8827

Abstract

Abstract : DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco–Sjogren and Wolcott–Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.