Explore the vast range of titles available.

Background X‐linked intellectual disability (XLID) is a genetically heterogeneous disorder that results in cognitive impairment and developmental delays. Mutations in the KDM5C gene have been identified as a causative factor in XLID. This study aimed to identify novel variants associated with XLID and to investigate the clinical and genetic characteristics of XLID patients with mutations in the KDM5C gene. This study also conducted a narrative review of the literature to identify key clinical and genetic characteristics of XLID caused by mutations in the KDM5C gene. Study Design Whole‐exome sequencing was performed on the proband's DNA, and Sanger sequencing was used to confirm and analyze the identified variant in a 20‐month‐old male patient with motor and speech delays. Moreover, a comprehensive literature review was conducted to gather previously reported cases, providing insights into the molecular findings and clinical characteristics of this disorder. Results The study identified a novel variant, c.2704C>T:p.Gln902X, located in exon 19 of the KDM5C gene (NM_004187.5) using Whole exome sequencing (WES), highlighting the utility of this approach in identifying rare genetic disorders. The analysis also revealed the variable clinical features associated with KDM5C‐related disorders and identified missense variants as the most prevalent among the reported variants. Conclusions This study provides insights into the clinical and genetic characteristics of XLID associated with KDM5C gene mutations, highlighting the higher manifestation of seizures in males and also addressing the heterogeneity of phenotypes in females. It also identifies a novel pathogenic variant and emphasizes the importance of considering gender‐specific factors and further research to understand the underlying molecular mechanisms. CLINVAR Accession Number SCV004034082 This study provides insights into the clinical and genetic characteristics of XLID associated with KDM5C gene mutations.

Background Creatine Transporter Deficiency (CTD) is a rare X-linked disorder caused by pathogenic or likely pathogenic variants in the SLC6A8 gene, leading to a deficiency of cerebral Creatine. Clinically, CTD manifests as a complex neurodevelopmental disorder and is associated with Intellectual Disability (ID), language and socio-communicative impairments, behavioral challenges and, often, epilepsy. Methods This study was conducted in two phases: (i) An eSurvey was distributed among major Italian clinics specializing in rare neurometabolic diseases to create a national census of CTD patients, with extensive clinical data; (ii) A retrospective observational study was performed on patients who had undergone regular long-term follow-up using a consistent neuropsychological assessment and treatment protocol. Results We identified 18 CTD male patients, aged 18 months to 32 years at diagnosis. Within this cohort, 3 to 13 years follow-up clinical information was collected for 10 patients. A specific clinical protocol was applied to this subgroup, where a biochemical or 1 H-MRS diagnosis was confirmed in 8 patients (urine Creatine/Creatinine ratio > 1), while in the remaining 2 patients, genetic testing was diagnostic and neurochemical tests followed. 1 H-MRS consistently showed a decreased Creatine peak in all patients. All 10 patients exhibited ID with significant speech disorder, and 6 had epilepsy. The treatment protocol for this cohort involved oral Arginine supplementation. Conclusions Diagnosing CTD remains clinically challenging due to the often negative results from a first tier clinical diagnostic test for intellectual disability (ID) (i.e. family history, cytogenetic testing and Fragile X) and neuroimaging without spectroscopy. CTD should be carefully considered when investigating severe ID with autistic-like traits and significant speech impairment, with or without epilepsy. The Urine Creatine/Creatinine ratio assay is a quick initial diagnostic step, which can be corroborated by a brain MRI/ 1 H-MRS and molecular genetics. Even considering previouis literature findings, it is not yet possible, to demonstrate definite genotype-phenotype correlations, although a milder functional impairment has been suggested for missense SLC6A8 pathogenic or likely pathogenic variants. Treatment strategies supplementation with Creatine and its precursors have provided heterogeneous and inconsistent results. Recently proposed innovative therapeutic strategies such as lipophilic Creatine analogs and betaine supplementation in animal models need validation in human disease.

ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities. Studies from others investigated the role of ATRX in skeletal development by tissue-specific Atrx knockout. However, the impact of ATRX during early skeletal development has not been examined. Using preosteoblast-specific Atrx conditional knockout mice, we observed increased trabecular bone mass and decreased osteoclast number in bone. In vitro coculture of Atrx conditional knockout bone marrow stromal cells (BMSCs) with WT splenocytes showed impaired osteoclast differentiation. Additionally, Atrx deletion was associated with decreased receptor activator of nuclear factor κ-B ligand ( Rankl )/ osteoprotegerin ( Opg ) expression ratio in BMSCs. Notably, Atrx -deficient osteolineage cells expressed high levels of the neuropeptide cocaine- and amphetamine-regulated transcript prepropeptide ( Cartpt ). Mechanistically, ATRX suppresses Cartpt transcription by binding to the promoter, which is otherwise poised for Cartpt expression by RUNX2 binding to the distal enhancer. Finally, Cartpt silencing in Atrx conditional knockout BMSCs rescued the molecular phenotype by increasing the Rankl / Opg expression ratio. Together, our data show a potent repressor function of ATRX in restricting Cartpt expression during skeletal development.

Creatine is a critical metabolite used to buffer cellular energy demands in highly energetic tissues such as the brain and muscle. Genetic defects in endogenous creatine synthesis or transport across cellular membranes lead to a common set of phenotypes referred to as Cerebral Creatine Deficiency Syndrome (CCDS). The most common form of CCDS is Creatine Transporter 1 (CT1) Deficiency (CTD). It accounts for ~ 70% of cases and results from loss-of-function mutations in the X-linked gene SLC6A8 . Affected individuals suffer from intellectual disability, autistic-like behaviors, and epilepsy. There are currently no effective therapies for this disorder, but gene therapy has emerged as a potential approach. The two enzymes which comprise the endogenous creatine synthetic pathway (AGAT and GAMT) are selectively expressed by specific cell types throughout the body. However, after synthesized, creatine uptake relies on the protein product of SLC6A8 , CT1, to transport creatine into target cell types. We hypothesized that gene delivery of GATM (encoding AGAT) and GAMT into end-user cell types would bypass the need for CT1, allowing for intracellular synthesis of creatine. We tested this strategy in two human cell types: HEK293T cells and primary fibroblasts. Co-delivery of GATM and GAMT increased internal creatine concentrations by 7.6-fold in HEK293T cells and 12.3-fold in healthy control fibroblasts. We then employed this approach to primary fibroblasts from patients with CTD. This resulted in an up to 11.6-fold increase in intracellular creatine concentrations, far exceeding the intracellular concentration of creatine in healthy control fibroblasts. Importantly, overexpression of AGAT and GAMT resulted in proper targeting of these enzymes to their natural cellular compartment and did not impair the growth of patient fibroblasts. These findings establish gene therapy with GATM and GAMT as a potential strategy for patients with CTD.

Creatine transporter deficiency (CTD) caused by mutations in SLC6A8 encoding the creatine transporter (CRT), leads to cerebral creatine deficiency syndromes; however, the cellular impact of CRT loss remains unclear. In this study, we investigated the consequences of the G561R mutation by examining fibroblasts using proteomics and functional assays. We observed severe intracellular creatine deficiency (> 90% reduction), leading to impaired energy metabolism (low ATP and high ADP/ATP). Proteomic analysis revealed significant alterations in the mitochondrial and extracellular vesicle pathways. Our investigation revealed impaired mitochondrial oxidative phosphorylation, reduced spare respiratory capacity, elevated oxidative stress, and significant alterations in amino acid transporter activity. Protein misfolding associated with G561R exacerbated these deficits compared to the deletion model. These findings elucidate the key pathological mechanisms induced by the CRT-G561R mutation—including energy metabolic reprogramming, mitochondrial dysfunction, and cellular stress—which significantly contribute to our understanding of the pathogenesis of creatine transporter deficiency and suggest potential therapeutic targets.

Identifying causative variants in cis -regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1 CRE and TENM1 CRE , showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1 CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1 CRE as the likely basis of the XLID in this family. Tenm1 CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1 CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.

Background/Objectives: X-linked intellectual disability (XLID) is a highly heterogeneous disorder accounting for ~10% of all males with ID. Next-generation sequencing (NGS) has revolutionized the discovery of causal XLID genes and variants; however, many cases remain unresolved. We present a four-generation syndromic XLID family with multiple males exhibiting variable degree of ID, focal dystonia and epilepsy. Methods: Extensive cytogenetic and targeted genetic testing was initially performed, followed by whole-exome sequencing (WES) and short-read whole-genome sequencing (WGS). Apart from the routine NGS analysis pipelines, sequencing data was revisited by focusing on poorly covered/mapped regions on chromosome X (chrX), to potentially reveal unidentified clinically relevant variants. Candidate variant validation and family segregation analysis were performed with Sanger sequencing. Results: All initial diagnostic testing was negative. Subsequently, 300 previously reported “dark” chrX coding DNA sequences, overlapping 97 genes, were cross-checked against 29 chrX genes highly associated (p < 0.05) with ID and focal dystonia, according to Phenomizer. Manual inspection of the existing NGS data in two low-coverage regions, chrX:25013469-25013696 and chrX:111744737-111744820 (hg38), revealed a recurrent pathogenic ARX variant NM_139058.3:c.441_464dup p.(Ala148_Ala155dup) (ARXdup24) associated with non-syndromic or syndromic XLID, including Partington syndrome. Sanger sequencing confirmed ARXdup24 in all affected males, with carrier status in their unaffected mothers, and absence in other unaffected relatives. Conclusions: After several years of diagnostic odyssey, the pathogenic ARXdup24 variant was unmasked, supporting a genotype–phenotype correlation in the first Partington syndrome family in Cyprus. This study highlights that re-examining underrepresented genomic regions and using phenotype-driven tools can provide critical diagnostic insights in unresolved XLID cases.

Background X-linked intellectual disability-hypotonic facies syndrome-1 (MRXHF1) and Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome are caused by pathogenic variant in the ATRX gene, a member of the switch/sucrose non-fermentable (SWI-SNF) protein family that exhibits chromatin remodeling activity. These syndromes show a wide spectrum of clinical manifestations, such as distinctive dysmorphic features, mild-to-profound intellectual disability, motor development delay, seizures, urogenital abnormalities, and gastrointestinal disorders. Case presentation and literature review A 3-year-old boy from a Chinese non-consanguineous family was diagnosed with MRXHF1 by whole-exome sequencing. Comprehensive family history information was obtained. The Medline database was searched until 1st Aug 2023 for articles related to ATRX pathogenic variant. Data on gene/protein mutations and clinical symptoms were extracted. The proband showed intellectual disability, motor development delay, typical facial abnormalities, urogenital defect, behavior problems, and optical nerve dysplasia. A novel frameshift mutation c.399_400dup, (p.Leu134Cysfs*2) in the ATRX gene was the primary cause, which occurs right before the ATRXDNMT3-DNMT3L (ADD) domain of ATRX protein. Missense mutation is the most common variation type. The ADD and helicase-like domains are the most frequently affected domains. Epilepsy, congenital heart disease, urogenital defect, acoustic defect, and optical defect are more prevalent in patients with frameshift mutations compared to those with missense mutations. There are more urogenital defects with C-terminal frameshift mutations than with N-terminal frameshift mutations. Conclusion We described a novel frameshift mutation in the ATRX gene in a patient with MRXHF1 syndrome and summarized the genotype–phenotype relationship of ATRX pathogenic variant by variation type and affected protein domain. The regulatory mechanism underlying ATRX variant requires comprehensive analysis in future studies.

Background Rapid Whole Genome Sequencing (rWGS) is increasingly being used in neonatal intensive care units, as there is growing evidence that rare singe gene disorders present in the neonatal period and early identification can change management. While the diagnostic utility is increased with this broad testing, the possibility of unexpected findings also increases significantly. Here, we present a patient found to have three distinct genetic conditions through rWGS testing, with significant psychosocial and health consequences. Methods and Results This case report describes a patient who was identified with a form of chondrodysplasia punctata, as well as incidental findings of MECP2‐related disorder and Jacobs' syndrome. To our knowledge, this is one of the first documented cases of triple genetic diagnoses in the literature, underscoring the expanding clinical utility of rWGS. Conclusion Our patient represents a unique example of the utility of rWGS in the NICU setting. As two of the three conditions were unexpected results, his case is an important reminder of the possibility of unexpected findings for both providers and families. His case demonstrates the importance of pretest counseling and consenting processes, particularly in an acute setting. It also will add to our understanding of MECP2 variant presentations in males in the future. Neonate was found to have X‐linked chondrodysplasia punctata, MECP2‐related disorder, and mosaic Jacobs syndrome, highlighting the utility of advanced genetic testing in directing neonatal care and the complexity of managing multiple genetic diagnoses, while also adding to our understanding of the MECP2‐related disorder phenotypes in boys.

Börjeson–Forssman–Lehmann syndrome (BFLS) is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in the plant homeodomain finger protein 6 (PHF6) gene. Core features include developmental delay, intellectual disability, dysmorphic craniofacial characteristics, obesity, hypogonadism and digital anomalies. Orofacial clefting has not been recognised as part of the canonical phenotype and is rarely reported in association with BFLS. One cohort study listed cleft lip and/or palate as an uncommon feature without individual case details, and a separate report described a female with a nonsense PHF6 variant and clefting of the hard and soft palate. Here, we describe a BFLS female with a de novo missense PHF6 variant who presented with cleft palate. This case adds to the emerging evidence that clefting, though uncommon, may be a recurrent manifestation. It supports the inclusion of PHF6 in the genetic testing of patients presenting with syndromic orofacial clefting when accompanied by neurodevelopmental delay or dysmorphism.