A case report of a novel de novo variant in PPP2CA causing a neurodevelopmental disorder and epilepsy

A novel mutation in SETD1A is associated with early-onset epilepsy—a rare case report

This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.

RFX3 Pathogenic Variants as a Rare Cause of Infantile Epileptic Spasms Syndrome

This case expands the clinical spectrum associated with RFX3 variants, supporting a potential role in IESS and early neurodevelopmental disruption, and highlights the relevance of including RFX3 in the genetic evaluation of patients with IESS and co-occurring neurodevelopmental disorders.

[De novo variant in the ATP2B2 gene as a cause of neuropsychiatric developmental disorder].

The ATP2B2 is associated with the development of hereditary conditions, including ataxia, dystonia, and intellectual disabilities. Recent research has established a connection between the ATP2B2 gene and a newly identified disorder characterized by delays in mental, speech, and motor development. This article presents a case study involving a patient diagnosed with autism spectrum disorder and intellectual disability, who possesses a previously unreported heterozygous variant in the ATP2B2 gene. This variant results in the loss of the stop codon, potentially leading to an elongation of the protein chain (c.3732G>C/p.Ter1244TyrextTer137, NM_001001331.2). The findings also provide additional data on the phenotype associated with this novel ATP2B2-related neurodevelopmental disorder, thereby enriching the understanding of this rare condition.

Identifying the Potential Role of Missense KIRREL3 Variants in Neurodevelopmental Phenotypes: A Case Series.

Neurodevelopmental disorders encompass a large group of conditions, many of which can be explained by genetic variants. KIRREL3 has previously been associated with neurodevelopmental disorders and is expressed in the developing human basal ganglia and amygdala. Through GeneMatcher, which allows clinicians, families, and researchers to share information about novel gene variants, and the Simons Foundation Powering Autism Research (SPARK) project, we identified 26 individuals with different rare missense variants in KIRREL3, which were predicted to be damaging based on their REVEL score. All probands had neurodevelopmental diagnoses including autism spectrum disorder, global developmental delay, intellectual disability, or a learning disability. A full review of previous publications identified 10 rare KIRREL3 missense variants in 13 individuals who had at least one diagnosis of an autism spectrum disorder or intellectual disability. These findings highlight the potential role of KIRREL3 missense variants in neurodevelopmental disorders, which warrants further study.

A de novoNR2F1 c.330 C > A variant in Bosch-Boonstra-Schaaf optic atrophy syndrome presenting with early-onset developmental and epileptic encephalopathy

PPP1R21-Related neurodevelopmental disorder: Phenotypic delineation, variant spectrum, and pathophysiological mechanisms

PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy caused by dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex. To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay/intellectual disability was universal; hypotonia near-universal (22/25, 88%). Ambulation was delayed and ataxic when achieved; expressive language was minimal or absent. A recognizable coarse facial gestalt was observed with thick eyebrows, broad nasal bridge, thick lips, and low-set ears. Systemic features included feeding dysfunction and respiratory morbidity requiring gastrostomy or tracheostomy in severe cases. Mortality was 17% (4/24). Neuroimaging showed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia. Patient fibroblasts showed delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation. PPP1R21-NDD is a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction. Diagnosis should be pursued with exome or genome sequencing in patients with characteristic clinical and neuroimaging features, particularly in consanguineous families. Research priorities include natural history studies, standardized magnetic resonance imaging (MRI) protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.