Comprehensive screening shows that mutations in the known syndromic genes are rare in infants presenting with hyperinsulinaemic hypoglycaemia

Abstract

SummaryObjectiveHyperinsulinaemic hypoglycaemia (HH) can occur in isolation or more rarely feature as part of a syndrome. Screening for mutations in the “syndromic” HH genes is guided by phenotype with genetic testing used to confirm the clinical diagnosis. As HH can be the presenting feature of a syndrome, it is possible that mutations will be missed as these genes are not routinely screened in all newly diagnosed individuals. We investigated the frequency of pathogenic variants in syndromic genes in infants with HH who had not been clinically diagnosed with a syndromic disorder at referral for genetic testing.DesignWe used genome sequencing data to assess the prevalence of mutations in syndromic HH genes in an international cohort of patients with HH of unknown genetic cause.PatientsWe undertook genome sequencing in 82 infants with HH without a clinical diagnosis of a known syndrome at referral for genetic testing.MeasurementsWithin this cohort, we searched for the genetic aetiologies causing 20 different syndromes where HH had been reported as a feature.ResultsWe identified a pathogenic KMT2D variant in a patient with HH diagnosed at birth, confirming a genetic diagnosis of Kabuki syndrome. Clinical data received following the identification of the mutation highlighted additional features consistent with the genetic diagnosis. Pathogenic variants were not identified in the remainder of the cohort.ConclusionsPathogenic variants in the syndromic HH genes are rare; thus, routine testing of these genes by molecular genetics laboratories is unlikely to be justified in patients without syndromic phenotypes.

Hyperinsulinemic Hypoglycemia Diagnosed in Childhood Can Be Monogenic

“…Second, while we screened the most common causes of HI (accounting for 69.8% of cases) we did not screen all known genetic causes of HI. We may therefore have missed pathogenic variants in the genes reported to cause syndromic HI; however, this would only have a small impact since they are expected to be rare ( 27 ). Insulinomas are a well-recognized cause of HI, with the youngest reported age at diagnosis being 2 years ( 28 ); while evidence of this as an underlying cause led to exclusion, they were not systematically screened for in our cohort.…”