Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical Case Description

The diagnosis of early infantile epileptic encephalopathy (EIEE) remains challenging, and next-generation sequencing (NGS) techniques have played a key role in identifying genetic causes. Recent studies have shown an association between mutations in the CYFIP2 gene and EIEE, with 20 deleterious variants reported so far and a de novo mutational hotspot at codon 87. A male infant presented with seizures since the age of four months as well as significant developmental delay and microcephaly. The seizures were of different types, frequent and refractory to treatment, including different anticonvulsant drugs. Metabolic studies showed no significant changes. The initial electroencephalogram revealed bilateral paroxysmal activity with hemispherical diffusion. Brain MRI showed no pathological changes. Analysis of a whole exome sequencing (WES) based multigene panel for epilepsy disclosed a heterozygous CYFIP2 gene variant [c.258_266del; p.(Trp86_Ser88del)] established as de novo. We describe the case of an infant with EIEE due to a de novo heterozygous in-frame deletion of three amino acids in CYFIP2: c.258_266del; p.(Trp86_Ser88del). This in-frame deletion eliminates codon 87, a mutational hotspot associated with a particularly severe EIEE phenotype. All previous reports had missense variants with a presumably gain-of-function mechanism. The clinical picture of our patient is very similar to the ones with deleterious variants affecting codon 87 reported in the literature. Our case report is the first to describe a disease-causing in-frame deletion in CYFIP2 and reiterates a consistent genotype-phenotype correlation.info:eu-repo/semantics/publishedVersio

Hemophagocytic lymphohistiocytosis in an adolescent with NLRP12-related autoinflammatory disorder—A case report

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Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

Funding Information: The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020). Funding Information: We thank our colleagues at “Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, Instituto de Investigacão e Inovacaão em Saúde, Porto” and Laboratory of Immunology, NOVA Medical School, Lisboa. The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020). Publisher Copyright: Copyright © 2022 Castro, Maia, Batalha, Freixo, Martins, Neves, Cordeiro and Neves.DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling.publishersversionpublishe