June 2, 2023

A Case Report: Developmental and Epileptic Encephalopathy in a Young Italian Woman with a De Novo Missense Variant in the CLCN4 gene

Jessica Rossi, Marco Russo, Giuseppe Gobbi, Alessandra Terracciano, Roberta Zuntini, Stefano Giuseppe Caraffi, Antonio Novelli, Livia Garavelli, Franco Valzania, Romana Rizzi

Raynaud-Claes syndrome is a rare X-linked intellectual developmental disorder caused by CLCN4 causative variants. The ClC-4 protein, encoded by this gene, presumably plays a role in ion homeostasis and intracellular trafficking. This protein is abundantly expressed in the hippocampus and cerebellum. Pathogenic CLCN4 variants lead to intellectual disability, epilepsy, behavioral issues, dysmorphic features, and progressive ataxia. Both loss-of-function and gain-of-function variants have been reported. This study presents a case of a young female with Raynaud-Claes syndrome caused by a de novo heterozygous CLCN4 gene variant (p.Gly544Arg).


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Informed consent was obtained from the proband’s parents for genetic testing. Whole-exome sequencing (WES) trio analysis was performed using the Twist Human Core Exome Kit on a NovaSeq6000 platform. The obtained reads were aligned to build GRCh37, and variant calling was done with the Dragen Germline Enrichment application. Variant annotation utilized the Geneyx Analysis (Knowledge-Driven NGS Analysis tool powered by the GeneCards Suite) platform. Variants were filtered and assessed based on recommended criteria. The Integrative Genome Viewer aided in visualizing the variants. X chromosome inactivation pattern was determined through analysis of 4 loci.

A 24-year-old female with developmental and epileptic encephalopathy presented with a seizure disorder starting at six months of age. The seizures progressed from myoclonic to tonic-clonic, impaired awareness seizures. The patient also had hypotonia, autistic regression, motor stereotypies, speech delay, and physical characteristics such as obesity, short stature, and a round face. MRI showed cranio-encephalic and mesial temporal lobe asymmetry, while EEG revealed abnormal frontal activity and spike/polyspike wave discharges.



Genome Analysis: CLCN4



Above: The de novo heterozygous nucleotide transition c.1630G>A in the CLCN4 gene (NM_001830.4) resulting in the amino acid substitution p.Gly544Arg (rs587777161) affects an evolutionarily conserved amino acid residue in the helical transmembrane domain of the protein and is predicted in silico to be damaging.

Initial tests, including karyotype, CGH array, and methylation analysis, did not identify the cause of the patient’s disease. However, trio-based WES uncovered a de novo heterozygous variant in the CLCN4 gene (p.Gly544Arg), affecting a conserved amino acid and predicted to be harmful. This variant is absent in control populations and has been associated with Raynaud-Claes syndrome in two males, indicating its pathogenicity. X-inactivation studies in the patient’s blood lymphocytes showed a random pattern.

In summary, the patient reported here had drug-resistant epilepsy, developmental delay, absence of speech, and behavioral impairment, consistent with Raynaud-Claes syndrome. CLCN4 gene variants have been associated with loss of ClC-4 protein function. Females, although affected less frequently, can have severe symptoms. The patient’s clinical features align with male cases, but worsened during the catamenial phase. Monitoring antiepileptic therapy during the fertile period is recommended. Symptomatic management is the current approach for Raynaud-Claes syndrome. Phenotypic characterization of CLCN4 gene variants is crucial for early intervention.


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