Jun 2026· Frontiers in Genetics· Vol 17· 0 citations· 31 references
Medicine
TL;DR
A role for EHMT2 in an autosomal recessive neurodevelopmental disorder is supported and anticipatory guidance for the patient’s family is allowed.
Abstract
Background EHMT1 and EHMT2 encode histone methyltransferases that form an epigenetic complex mediating mono- and dimethylation of histone H3 at lysine 9 (H3K9me1/2). This complex modulates fundamental biological processes during embryonic and post-natal development. While EHMT1 has an established role in neurodevelopmental disease, with heterozygous pathogenic variants causing Kleefstra syndrome type 1 (KS1), the contribution of EHMT2 to neurodevelopmental disorders remains to be established. To date, seven probands harboring de novo heterozygous EHMT2 variants and one individual with a homozygous splice variant have been reported, all presenting with phenotypes and DNA methylation episignatures overlapping with KS1. Methods A male proband was referred for Genetics evaluation due to global developmental delay, autism spectrum disorder, hypotonia, dysmorphisms, posterior fossa malformation, congenital heart disease, umbilical hernia, and genitourinary anomalies. Trio genome sequencing identified compound heterozygous variants in EHMT2 (NM_006709.5:c.2648_2649del; p.(Glu883Glyfs*48), paternally inherited; NM_006709.5:c.2344-19_2344-16del; r.spl, maternally inherited). DNA methylation episignature profiling and RNA-sequencing were performed to assess the molecular consequences of these EHMT2 variants. Results Proband phenotype strongly overlapped with that of KS1 and previously reported individuals with autosomal dominant and recessive EHMT2-related neurodevelopmental disorder. DNA methylation episignature was consistent with KS1. Transcripts bearing the paternally inherited EHMT2 frameshift variant were under-represented in the RNA-sequencing data, likely reflecting partial nonsense-mediated decay. The maternally inherited EHMT2 variant causes multiple aberrant splicing events in a subset of transcripts (∼25%), including retention of 291 nucleotides from intron 18, which generates a nonsense variant in the canonical EHMT2 transcript. Conclusion Our findings support a role for EHMT2 in an autosomal recessive neurodevelopmental disorder and allowed anticipatory guidance for the patient’s family.
Background: Pathogenic variants in the PPP1R12A gene have been associated with a malformation syndrome involving the brain and the genitourinary systems (GUBS, MIM #618820). To date, neither hearing loss (HL) nor inner ear malformations have been reported in affected individuals, and these features are therefore not currently regarded as part of the PPP1R12A-related phenotype. Moreover, functional evidence supporting the pathogenicity of several reported variants remains limited. Methods: We investigated a 12.5-year-old patient presenting with profound bilateral sensorineural hearing loss associated with inner ear malformations, genitourinary and central nervous system abnormalities. The patient underwent comprehensive clinical, audiological and radiological assessments, followed by genetic testing via trio-based whole-exome sequencing (WES). The molecular consequences of the identified variant were evaluated through minigene splicing assay and RT–PCR analysis on RNA extracted from peripheral blood cells. Results: WES identified a novel heterozygous splicing variant (c.792+3A>C) in the PPP1R12A gene (NM_002480.3). Functional studies demonstrated that this variant causes complete skipping of exon 5, resulting in a frameshift and the introduction of a premature termination codon. RT–PCR analysis confirmed the presence of the alternatively spliced transcript lacking exon 5. In addition, an extensive review of the literature indicated that no clear genotype–phenotype correlation has yet been established for PPP1R12A-related disorders and, whereas the majority of previously reported patients share brain and genitourinary malformations our patient additionally presented with profound bilateral sensorineural HL and inner ear malformations. Conclusions: Our findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and we further propose that HL and inner ear malformations may represent novel features associated with this clinical spectrum. Moreover, our study underscores the importance of functional studies for accurately defining the molecular consequences of novel variants and establishing appropriate clinical correlations.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 0 citations
PURPOSE
Pathogenic variants in CNKSR2 (Xp22.12) cause an X-linked neurodevelopmental disorder with intellectual disability, language impairment, and a distinctive epilepsy phenotype, including encephalopathy with status epilepticus during slow-wave sleep (ESES/CSWS). Hemizygous males are typically severely affected, whereas symptomatic females remain rare and incompletely characterized. We describe two unrelated patients with de novo CNKSR2 variants to expand the mutational and sex-dependent phenotypic spectrum of this disorder.
METHODS
Both patients underwent clinical, electroencephalographic, and neuroimaging evaluation. CNKSR2 variants were identified by whole exome sequencing with parental segregation, and the splice-site variant was assessed in silico (SpliceAI, MaxEntScan, Human Splicing Finder).
RESULTS
Patient 1, a 17-year-old female, harbored a novel canonical splice-site variant (c.64+1G>A) in the N-terminal region and presented with a relatively mild phenotype. In silico analysis supported abolition of the canonical donor splice site. Patient 2, an 8-year-old male, carried a de novo nonsense variant (c.2185C>T, p.Arg729*) and exhibited drug-resistant ESES, autism, and severe language impairment. p.Arg729* had previously been reported in one independent male. Our case represents its second independent occurrence, a CGA>TGA transition at a CpG dinucleotide consistent with a mutational hotspot.
CONCLUSION
Together, these cases expand the mutational spectrum and provide further evidence for sex-dependent phenotypic variability in CNKSR2-related epilepsy. Our observations support the hypothesis that X-chromosome inactivation may contribute to phenotypic variability in females, although XCI was not assessed here, and support inclusion of CNKSR2 in epilepsy gene panels regardless of sex.
Adnan Deniz, Eyyüp Üçtepe, F. M. Sönmez· Seizure· 0 citations
The findings support the pathogenicity of this variant and further expand the pathogenic variant spectrum of the PPP2CA gene, and the observed genotype–phenotype correlation provides valuable information for prognosis and genetic counseling.
Lei Xu, Yanfeng Shen, Guixiang Zhang· Frontiers in Psychiatry· 0 citations
Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.
Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
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.
N. Kastratović, Marina Gazdić Janković, Marina Miletić Kovačević et al.· International Journal of Mol...· 0 citations
Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males, and its pathogenicity was evaluated using a molecular dynamic simulation and transgenic Drosophila models.
Kazuyuki Komatsu, Atsushi Sugie, Yohei Nitta et al.· European Journal of Human Ge...· 1 citation