Jul 2026· Sultan Qaboos University Medical Journal· Vol 26, pp. 448 - 454· 0 citations· 24 references
Medicine
TL;DR
Clinical heterogeneity among children with NRXN1 deletions illustrates clinical heterogeneity among children with autism spectrum disorder and supports the need for larger studies to better define genotype-phenotype relationships.
Abstract
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.
A retrospective multicenter case series of seven previously unreported individuals with heterozygous FBXW7 variants identified through clinical genetic testing expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance.
Salvatore Savasta, F. Comisi, G. Dell’Isola et al.· Journal of Neurodevelopmenta...· 0 citations
Background: Epilepsy and behavioral disorders in children can result from various genetic etiologies. We report the case of a child with refractory epilepsy and behavioral disturbances in whom two rare variants were identified in the SLC2A1 and SMC1A genes. This case highlights the importance and challenges of early molecular diagnosis in resource-limited African settings. Case Presentation: A male child presented with early-onset epilepsy and significant behavioral disturbances. Neurological examination showed no malformations. Brain MRI was normal. Sleep EEG revealed no interictal epileptiform activity. Psychomotor assessment indicated hyperactivity, attentional deficits, fine and gross motor difficulties, and opposition to limits. Initial developmental screening was performed using the Denver Developmental Screening Test II, which showed mild delay in fine motor coordination and expressive language. A subsequent comprehensive evaluation using the Bayley Scales of Infant and Toddler Development, 3rd edition, confirmed a global psychomotor delay predominantly affecting coordination and attention. Genetic analysis from a buccal swab using targeted next-generation sequencing revealed two heterozygous rare variants: SLC2A1 c.580_585del (p. Phe194_Ile195del) and SMC1A c.2414A>G. These variants have not been previously reported in African literature. The patient received adapted antiepileptic therapy and multidisciplinary follow-up. Conclusion: This case illustrates the exceptional coexistence of SLC2A1 and SMC1A variants and underlines the value of early molecular diagnosis even in resource-limited contexts, to guide personalized management.
Kouakou Kouamé Cyprien, Doumbia-Ouattara Mariam, Dainguy Marie Evelyne et al.· Journal of Pediatric Genetic...· 0 citations
Background 3q29 deletion syndrome is a rare genomic disorder characterized by a broad spectrum of neurodevelopmental and psychiatric manifestations, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and a markedly increased lifetime risk of psychosis and schizophrenia. Case presentation We describe a 17-year-old female adolescent with severe congenital heart disease and longstanding neurodevelopmental impairment who developed early-onset recurrent psychotic symptoms. Chromosomal microarray analysis identified a de novo heterozygous 1.6 Mb deletion at the 3q29 locus. The emergence of psychotic symptoms served as the pivotal clinical trigger for genetic investigation in the absence of distinctive dysmorphic findings. Combination therapy with lurasidone and olanzapine led to sustained clinical stabilization over a one-year follow-up period, allowing gradual dose adjustment and functional reintegration through adapted educational and recreational activities. Conclusions Early-onset psychotic symptoms in adolescents with neurodevelopmental comorbidities may represent a critical clinical indicator of underlying pathogenic copy number variants, including 3q29 deletion syndrome, even in the absence of highly recognizable dysmorphic features. Increased clinical awareness may facilitate consideration of early genetic testing in this clinical profile to support precision-informed diagnostic evaluation, treatment planning and multidisciplinary management.
E. Bartolini, Federica Iannotta, W. Vidal et al.· Frontiers in child and adole...· 0 citations
BACKGROUND
Autism spectrum disorder (ASD) is a neurodevelopmental condition including incorrect functioning in communication, social interaction, and repetitive behavior. Global prevalence is estimated as 1-2%, with a predominance of men. Different pre- and perinatal, environmental, immunological, neurobiological, genetic, and epigenetic factors are involved in the etiology of ASD. The study aims to analyze genetic abnormalities in patients with ASD according to data from the current literature.
MATERIALS AND METHODS
Studies available in the PubMed and Google Scholar databases were chosen through a literature search. Only papers published from 2020, available as full-text publications in English, with studies conducted on humans, original papers, or meta-analyses were included.
RESULTS AND DISCUSSION
The following types of genetic variation were identified: copy number variants, larger insertions, inversions, uniparental disomies, tandem repeat expansions, common single nucleotide polymorphisms, single nucleotide variants, short insertions/deletions, and mitochondrial variants. Epigenetic factors, like histone modifications, deoxyribonucleic acid (DNA) methylation, and micro ribonucleic acid might play an important role in ASD predisposition. Genes identified in the review were mainly involved in neurodevelopment, synaptic formation, neuronal migration, neurotransmission, glial proliferation, ubiquitination, chromatin remodeling, or transcription. ASD is described as a component of the phenotype in fragile X syndrome, tuberous sclerosis complex, neurofibromatosis type 1, Angelman, Phelan-McDermid, Smith-Lemli-Opitz syndromes, and chromosome trisomies. Current guidelines for genetic diagnosis of ASD recommend performing directed genetic studies in the first line (like multiplex ligation-dependent probe amplification - MLPA, analysis of FMR1 gene), in case of a negative result, chromosomal microarray as a routine method, then next-generation sequencing (NGS) panel testing, WES (whole exome sequencing), or even WGS (whole genome sequencing) as the last test.
CONCLUSIONS
Wider access to modern diagnostic methods has increased the number of ASD patients in whom the genetic etiology of the disorder has been uncovered. Knowledge of the genetic background would be applicable in the diagnosis, prevention, prognosis, and individualized treatment.
G. Ręka, Katarzyna Wojciechowska, Monika Lejman· BMC Medical Genomics· 0 citations
Current knowledge on the genotypic and phenotypic spectra of SET-NDD is expanded, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.
Angelo Condell, Elaine Zhang, Tim Sikora et al.· Clinical Genetics· 0 citations
A developmental language disorder (DLD) is a neurobiological condition characterized by impaired language development despite adequate linguistic input and normal intelligence. The role of monogenic causes in the pathogenesis of DLD is largely unknown and diagnostic genetic testing is rarely offered. This study assessed the diagnostic yield of genome sequencing in severe DLD and investigated the underlying genetic foundations. We designed a prospective cohort study involving trio-based genome sequencing in 25 individuals (aged 3-25 years) with severe DLD, no intellectual disability (non-verbal IQ ≥ 70), no autism spectrum disorder diagnosis and no first-degree family history of DLD or neurodevelopmental disorders. (Likely) pathogenic variants were found in nine of 25 individuals, reflecting a molecular diagnostic yield of 36%. The genetic causes were diverse and involved seven autosomal dominant disorders, one autosomal recessive disorder, and one sex chromosome aneuploidy. In seven individuals, the disease-causing variant occurred de novo. All identified (likely) pathogenic variants were located in genes or loci that have been previously implicated in neurodevelopmental disorders with variable clinical presentations. Importantly, the genetic diagnosis provided actionable insights for counselling and clinical follow-up for all nine individuals. This study reveals a high prevalence of rare (mainly de novo) genetic variants in individuals with severe and sporadic DLD, and demonstrates extensive molecular overlap with other neurodevelopmental disorders. Our results support the implementation of routine trio-based genetic testing in individuals with severe and sporadic DLD.
Milou G. P. Kennis, Leenke van Haaften, K. van Hulst et al.· European Journal of Human Ge...· 0 citations