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Intrafamilial Variability in NRXN1-Associated Neurodevelopmental Disorders: Clinical and Genetic Insights from a Family Case Study with Literature Review
The concept that NRXN1 deletions alone do not determine clinical outcome but rather act within a broader genetic and biological context is supported, whereby NRXN1 deletions act as susceptibility factors whose phenotypic consequences are shaped by additional genetic and modifying influences.
Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.
An integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.
Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.
The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.
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.
Deciphering the Role of LNX2 as a Potential Contributor to Neurodevelopmental Disorders
The biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders is supported, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs.
Clinical Phenotypes Associated with NRXN1 Deletions in Five Children with Autism Spectrum Disorder in Oman
Summary NRXN1 (2p16.3) is essential for synaptic function and has been implicated in autism spectrum disorder (ASD) and other neurodevelopmental disorders. However, the phenotypic features associated with NRXN1 copy number variants remains incompletely characterised, which complicates risk assessment in genetic counselling. This case series describes five children, who were evaluated at the Genetics and Developmental Pediatrics Clinic of a tertiary care hospital in Muscat, Oman, from 2011 to 2023, with rare NRXN1 deletions (57–150 kb). All met DSM-5 criteria for ASD and had speech and language delays with cognitive impairment. Consanguinity was reported in three of the families and two had a family history of ASD. Microcephaly was present in four children and one showed facial dysmorphism. Generalised tonic-clonic seizures were present in one child and one child had comorbid attention deficit hyperactivity disorder. These findings illustrate clinical heterogeneity among children with NRXN1 deletions and supports the need for larger studies to better define genotype-phenotype relationships.