Prenatal diagnosis of CLCN4-related neurodevelopmental disorder in fetuses with congenital brain anomalies.

We report two male fetuses born to a healthy unrelated couple, with agenesis of the corpus callosum identified on detailed 20-week ultrasound scans and confirmed by in-utero MRI. Whole-genome sequencing identified a likely pathogenic missense variant in the CLCN4 gene, establishing this as the causative gene in the family. Pathogenic variants in the CLCN4 gene cause a neurodevelopmental disorder (also called Raynaud-Claes syndrome) inherited in an X-linked pattern. The disorder is characterised by developmental delay, intellectual disability, autism spectrum disorder, epilepsy, mental health conditions, and significant feeding difficulties, predominantly, but not exclusively, affecting males. This is the first report of a prenatal phenotype associated with variants in the CLCN4 gene. The diagnosis of the CLCN4-related neurodevelopmental disorder in this family allowed accurate genetic counseling and discussion of reproductive choices. This leaves uncertainty about the possibility of a postnatal neurodevelopmental phenotype in heterozygous females, which we discuss.

Prekallikrein - an emerging therapeutic target for Klebsiella pneumoniae infection?†.

Klebsiella pneumoniae is a Gram-negative bacterium that is increasingly difficult to treat due to the emergence of multidrug resistant strains. In a recent article, Ding et al demonstrate that prekallikrein depletion in mice followed by intranasal instillation of K. pneumoniae leads to a reduced bacterial burden and prolonged host survival, together with evidence of reduced distant organ damage. These effects are apparently independent of the role of prekallikrein in the contact system, and are associated with transcriptional changes relevant to innate immunity in the lung, established prior to infection. This study highlights the importance of further investigating the role of prekallikrein and other contact cascade components in host defence to counter K. pneumoniae (and perhaps other pathogens), with an overall aim of identifying potential therapeutic targets relevant to pulmonary infection with such resistant pathogens. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genetic testing in patients with possible foetal alcohol spectrum disorder.

OBJECTIVE: To assess the diagnostic yield of genetic conditions in patients referred to a regional genetics service to consider a diagnosis of foetal alcohol spectrum disorder. DESIGN: Retrospective case series. SETTING: A regional genetics centre in Yorkshire. PATIENTS: All referrals to the Yorkshire Regional Genetics Service coded with mentions of maternal alcoholism or foetal alcohol were considered for inclusion. Exclusion criteria were follow-up patients, patients with missing case notes and patients failing to attend their appointment. METHODS: Medical records were reviewed and the following information was extracted: referring specialty, reason for referral, gender, age at assessment by clinical genetics, accompanying individual, history of alcohol exposure in pregnancy, clinical examination details, neurodevelopmental deficits, genetic testing prior to referral, genetic testing organised by the genetics department and diagnosis made by clinical genetics. RESULTS AND CONCLUSION: 110 patients were included. 130 tests were carried out, including 86 array comparative genomic hybridisation tests. The overall diagnostic rate for a contributing genetic disorder was 3.6%, all being chromosomal disorders and chromosome copy number variants.

Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants.

With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220. He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.