DESIGN: We 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.

PATIENTS: We undertook genome sequencing in 82 infants with HH without a clinical diagnosis of a known syndrome at referral for genetic testing.

MEASUREMENTS: Within this cohort, we searched for the genetic aetiologies causing 20 different syndromes where HH had been reported as a feature.

RESULTS: We 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.

OBJECTIVE: To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.

METHODS: We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.

RESULTS: Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.