Huyghebaert J, Christiaenssen B, De Rademaeker M
… +5 more, Van den Ende J, Vandeweyer G, Kooy RF, Mateiu L, Annear D
Eur J Med Genet
· 2025 Jun · PMID 40057302
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In this study, we employed a multifaceted approach combining short-read whole genome sequencing (WGS) analyzed using Delly, cytogenomics using Bionano technology, and Sanger sequencing to identify the breakpoints of a ba...In this study, we employed a multifaceted approach combining short-read whole genome sequencing (WGS) analyzed using Delly, cytogenomics using Bionano technology, and Sanger sequencing to identify the breakpoints of a balanced de novo paracentric inversion on chromosome 11, spanning approximately 64 Mb (inv11q13.3; q25). This inversion was discovered in a girl who presented with mild intellectual disability (ID), speech and language delays, a delay in motor development and attention deficit hyperactivity disorder (ADHD). Detailed analysis of the breakpoints revealed the disruption of two genes; SHANK2, which is critical for encoding a postsynaptic scaffolding protein at glutamatergic synapses in the brain, and LINC02714, a long non-coding RNA (lncRNA). Although SHANK2 is not listed in the OMIM database as a causative gene to this date, literature reports at least 21 cases where (likely) pathogenic variants in SHANK2 have been identified in patients with neurodevelopmental disorders (NDDs). A loss of function variant of the SHANK2 gene is in line with the clinical presentation of this patient. No additional genetic variants that could explain her phenotype were identified. In conclusion, by combining WGS, cytogenomics and Sanger sequencing techniques, we identified the exact breakpoints of a large inversion providing a likely molecular diagnosis for our patient.
Eur J Med Genet
· 2025 Jun · PMID 40043752
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Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous type-I interferonopathy presenting in infancy with intracranial calcifications, white matter lesions, and brain atrophy. AGS7, caused by gain-of-function (G...Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous type-I interferonopathy presenting in infancy with intracranial calcifications, white matter lesions, and brain atrophy. AGS7, caused by gain-of-function (GOF) mutations in the IFIH1 gene, triggers excessive type-I interferon production, leading to autoimmune responses. We describe an 18-year-old female diagnosed with AGS7 due to a somatic GOF mutation in IFIH1. In 2014, she presented with multiple joint swelling, facial rash, and hair loss, and received a diagnosis of juvenile idiopathic arthritis and systemic lupus erythematosus. Traditional immunosuppressants were administered, but provided little benefit. Genetic testing in 2023 revealed a GOF variant (p.R720G) in IFIH1. Given the link between IFIH1 variants and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, we administered tofacitinib (a JAK inhibitor) and oral methylprednisolone, with tapering of the traditional immunosuppressants. After nearly one year, the patient showed no significant disease activity and normal hair growth, with no notable changes in thyroid function. Although treatment of AGS remains challenging, this case suggests tofacitinib can successfully manage AGS7 symptoms. More clinical studies are needed to verify the long-term safety and efficacy of tofacitinib.
Genetic and genomic testing often have implications not only for the individual tested but also for their genetic relatives. This study aims to characterize public attitudes toward the familial disclosure of genetic risk...Genetic and genomic testing often have implications not only for the individual tested but also for their genetic relatives. This study aims to characterize public attitudes toward the familial disclosure of genetic risks. An online survey was completed by a sample of the Portuguese general population (n = 1034), assessing preferences for genetic testing, the receipt of genetic risk information, and the sharing of such information with family members. Results reveal a strong preference among respondents for receiving information on genetic risks and undergoing genetic testing. There was also ample agreement that family members should be informed about the risk of developing an inherited condition and undergo genetic testing. Additionally, participants expressed a preference for healthcare professionals to inform both themselves and their family members of genetic risks. Our findings suggest broad acceptance of the possibility for healthcare-mediated disclosure of genetic risks to family members. However, this approach to disclosure warrants further investigation, as direct contact with patients' relatives remains a contentious issue. A broad discussion is needed on how to best cascade relevant genetic information to patients' family members, taking into account the perspectives of all key stakeholders.
Eur J Med Genet
· 2025 Jun · PMID 40015599
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Bazex-Dupré-Christol syndrome is a rare genetic condition characterised by basal cell carcinomas, follicular atrophoderma and hypotrichosis. Until recently, the molecular basis of the condition was largely unknown. A rec...Bazex-Dupré-Christol syndrome is a rare genetic condition characterised by basal cell carcinomas, follicular atrophoderma and hypotrichosis. Until recently, the molecular basis of the condition was largely unknown. A recent study has identified a section of duplicated DNA on the X chromosome of those with the condition which appears to be the underlying cause of the syndrome. This case study looks at a family with five affected members over three generations. They had been diagnosed with the syndrome in early life and had previously undergone genetic testing with no cause being found. The index patient within this family has now been identified as having the same duplication as those tested in the initial study.
Two major psychiatric disorders, schizophrenia and bipolar I disorder, are regarded as distinct disorder entities; however, they share intricate connections through characteristic overlap and underlying genetic aetiology...Two major psychiatric disorders, schizophrenia and bipolar I disorder, are regarded as distinct disorder entities; however, they share intricate connections through characteristic overlap and underlying genetic aetiology, challenging the traditional dichotomy. This convergence emerged as an essential area of investigation in understanding the genetic determinants of schizophrenia and bipolar I disorder. Moreover, psychiatric genetic research has revealed demographic disparities, with South African population groups notably underrepresented. Therefore, this preliminary targeted candidate gene association study of 20 single nucleotide polymorphisms implicated in schizophrenia and bipolar I disorder aimed to investigate association and overlap. Candidate loci for schizophrenia and bipolar I disorder were selected through an exploratory Illumina® Infinium PsychArray-24 analysis combined with literature and database searches. Genotyping of the selected loci was performed with the Agena Bioscience MassARRAY® platform on 96 cases (58 schizophrenia and 38 bipolar I disorder patients) and 44 controls of Afrikaner, Sotho, and Tswana descent. Association analysis was performed by comparing and combining population and phenotype groups. Significant (p < 0.05) loci in the ADAMTSL1, CACNA1B, CACNA1C, CDH13, CTNNA2, RBFOX1, and TRIO genes were identified as possible susceptibility factors, and differences were observed with the association between population and phenotype groups. Through further pathway analysis, the calcium and cadherin-catenin pathways were identified as possible role players in the aetiology of schizophrenia and bipolar I disorder. The study represented an essential step towards understanding the genetic contribution towards schizophrenia and bipolar I disorder in distinct population groups and has the potential to contribute towards the knowledge base and inform future research efforts.
INTRODUCTION: Familial hypercholesterolemia (FH) affects around 1 in 250 people. Most FH cases are caused by pathogenic LDLR variants, with copy number variations (CNVs) accounting for about 10 %. However, short-read gen...INTRODUCTION: Familial hypercholesterolemia (FH) affects around 1 in 250 people. Most FH cases are caused by pathogenic LDLR variants, with copy number variations (CNVs) accounting for about 10 %. However, short-read gene panel sequencing and multiplex ligation-dependent probe amplification (MLPA) are limited in the specification of CNV breakpoints and the identification of complex structural variants (SVs). MATERIALS AND METHODS: We designed crRNAs for Cas9-mediated target selection of LDLR and performed long-read sequencing (LRS) on an Oxford Nanopore MinION device using high-molecular-weight (HMW) DNA or DNA from standard purification. After establishing the LRS approach, we characterized two known LDLR CNVs and tested two individuals with strong clinical evidence of FH but no pathogenic variant in short-read gene panel sequencing. RESULTS: Complete coverage of LDLR was achieved for both HMW DNA and DNA from standard purification. LRS allowed us to specify CNV breakpoints and showed that the known LDLR deletion is 19.2 kb in size encompassing exons 1-2 and the 5'-untranslated and promoter regions. Furthermore, LRS verified the in tandem localization of a large LDLR duplication covering exons 4-8. Both CNVs were classified as loss-of-function. Moreover, breakpoint information enabled confirmatory analysis by PCR and Sanger sequencing for both CNVs. No SVs were detected in two apparently mutation-negative FH probands using our approach. CONCLUSIONS: Nanopore LRS with CRISPR/Cas9-mediated target selection allows for accurate characterization of CNVs and can therefore serve as a complementary method to short-read sequencing-based FH diagnostics by facilitating variant interpretation and enabling cost-effective PCR-based variant confirmation in subsequent familial analyses.
Autism Spectrum Disorder (ASD) is to date considered a disorder with a complex aetiology that recognizes both genetic and environmental risk factors. The role of the genetic contribution is progressively and significantl...Autism Spectrum Disorder (ASD) is to date considered a disorder with a complex aetiology that recognizes both genetic and environmental risk factors. The role of the genetic contribution is progressively and significantly increasing, and lately thousands of genes have been linked to ASD. In this clinical report we describe a child with ASD carrying a heterozygous novel missense variant p.Arg987Trp in the ANK2 gene in heterozygous state, predicted pathogenic, and inherited from her father. The ANK2 gene has been associated with ASD but to date just few reports described the related phenotypes thus we aim at expanding behaviours endophenotypes of familial ANK2-related condition. Our patient was diagnosed with high-functioning ASD while her father showed subthreshold autistic traits such as relational difficulties and peculiar interests. We present this familial case to study genotype-phenotype correlation and highlight the huge variability of Autism spectrum phenotypes of the ANK2-related conditions. Nevertheless, future studies that can explore more of the link between the genetics of autism and associated clinical expressivity would be interesting.
Carrier screening for monogenic diseases is becoming increasingly important in preventive medicine, yet selecting appropriate target genes remains a complex task, especially in countries with significant ethnic and geogr...Carrier screening for monogenic diseases is becoming increasingly important in preventive medicine, yet selecting appropriate target genes remains a complex task, especially in countries with significant ethnic and geographic diversity such as China. This study aimed to develop a strategy to screen for carrier screening target genes suitable for the Chinese population, considering regional variations in carrier frequencies (CFs). We analyzed a dataset from a large-scale, multicenter carrier screening study, encompassing 33,104 individuals from different regions of China and carrier status for 223 genes. We focused on the CFs of these genes across regions. The study first stratified the population based on participants' self-reported ancestral places and then applied consensus k-means clustering analysis to the CF characteristics of these regions. This approach enabled us to identify distinct regional subpopulations with shared genetic backgrounds. The results showed that the regions clustered into three subpopulations (North, South, and Far South) based on CF characteristics, and 44 genes exhibited significant CF differences across these subpopulations (α = 0.05). Applying an overall CF threshold without considering regional diversity would have excluded 11 regionally prevalent genes from the screening panel. By incorporating regional variations, we accurately identified 58 genes that met the recommended CF criteria (autosomal gene CF > 1/200, X-linked gene CF > 1/40,000) in at least one subpopulation. This study emphasizes the importance of considering regional diversity when designing carrier screening panels for monogenic diseases in China. Our proposed strategy, combining regional stratification and clustering analysis, provides a more precise method for selecting target genes, thereby enhancing the effectiveness and relevance of screening programs across different Chinese populations.
Cases with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in...Cases with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a well-characterized population from northeastern France. The associated anomalies in CAKUT were collected in all live births, stillbirths and terminations of pregnancy during 29 years in 387,067 consecutive births of known outcome in the area covered by our population-based registry of congenital anomalies. Of the 1946 cases with CAKUT born during this period (prevalence at birth of 50.3 per 10,000), 653 (33.6%) had associated anomalies. There were 138 (7.1%) patients with chromosomal abnormalities including 39 trisomy 18 (2%), and 195 (10%) syndromic conditions including VA(C)TER(L) association (3.3%), Meckel-Gruber syndrome (2.1%), and prune belly syndrome (1.4%). Three hundred twenty (16.4%) of the cases had multiple congenital anomalies (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other non urinary anomalies. Prenatal diagnosis was obtained in 71.5% of the cases with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one out of three cases, emphasizes the need for a thorough investigation of cases with CAKUT. A routine screening for other non urinary anomalies may be considered in cases with CAKUT. One should be aware that the non urinary anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six cases with CAKUT.
Scientific advances in genomics are transforming healthcare and prevention. However, they also increase situations of uncertainty, which in turn increase vulnerability not only for patients and their families but also fo...Scientific advances in genomics are transforming healthcare and prevention. However, they also increase situations of uncertainty, which in turn increase vulnerability not only for patients and their families but also for professionals. Cardiogenetics plays a crucial role in preventing sudden death in young individuals, but it can pose complex challenges for healthcare teams. To study professionals' perspectives and experiences regarding cardiogenetics-related vulnerability, a national online survey was conducted in France to gather insight from professionals involved in the care pathway of individuals with cardiogenetic conditions. The survey targeted clinical geneticists, genetic counselors, cardiologists, nurses, and psychologists, in collaboration with the CARDIOGEN network. Out of 86 respondents, the majority (64%) reported experiencing vulnerability, which was not correlated with their profession, experience, or the organization of their clinics. Acknowledged vulnerabilities were mainly related to uncertainties regarding incomplete penetrance, variable expression, and genotype-phenotype disparities in cardiogenetics, exacerbated by the evolving interpretation of genetic data, due to the increased access to genomics. Additionally, the implications of these issues, particularly in cases of unexplained sudden deaths that necessitated genetic investigations and family follow up recommendations, raised further concerns. The reported vulnerabilities encompassed both the need for specialized knowledge and the structural complexities of teams combining skills in genetics and cardiology. In addition, the professionals' capacity to empathize can add a degree of vulnerability. Finally, it seems important to focus on how cardiogenetics teams are organized, particularly through close collaboration among genetics and cardiology units, which could help reduce this feeling of vulnerability.
Over two decades ago, a primigravid female presented with concern for recurrence of an adverse phenotype affecting her three brothers. The three brothers presented with intellectual disability, developmental delay, behav...Over two decades ago, a primigravid female presented with concern for recurrence of an adverse phenotype affecting her three brothers. The three brothers presented with intellectual disability, developmental delay, behavior problems and dysmorphic features. The screening tools available at the time revealed an FGD1 variant present in all three brothers, their mother being a carrier, absent in their unaffected uncle, and absent in the proband herself. This variant was hypothesized to be explanatory, but years later more advanced genetic screening showed that it was benign. Episign analysis revealed the true cause, a novel pathogenic KDM5C variant. This case study provides further insight into the KDM5C phenotype and demonstrates the importance of amending past errors as science evolves.
Genetic Counselling Supervision (GCS) plays an integral role in professional development, stimulating reflective practice and helping to prevent burnout. Nevertheless, evidence points to insufficient practice of GCS. Thi...Genetic Counselling Supervision (GCS) plays an integral role in professional development, stimulating reflective practice and helping to prevent burnout. Nevertheless, evidence points to insufficient practice of GCS. This study aimed to explore the current state of counselling supervision access during MSc training, along with barriers and facilitators for its implementation. MSc coordinators of the current EBMG accredited programmes were invited to participate in this study via email, with the request to fill out a questionnaire. The qualitative data obtained was reviewed using thematic analysis, while descriptive statistics was used for the quantitative data. GCS was considered crucial for fostering professional development, safe practice, and emotional support for the future professionals. While all MSc programmes included counselling supervision in their course curricula, its implementation was highly heterogeneous. Students have access to GCS during clinical placements in 62,5% of the programmes, facilitated by institutional support and EBMG guidelines. Several barriers hindered its broader implementation, as was the case of a shortage of senior genetic counsellors and the lack of professional recognition in some countries. This study compiled evidence of the insufficient practice of GCS across Europe and its limited integration in MSc programmes. Therefore, we recommend educational pathways actively promote genetic counselling supervision routines to ensure graduates enter the workforce with the necessary tools to provide care with the expected standard of safety and quality, while maintaining a reflective practice.
Pathogenic variants in VPS53 are associated with pontocerebellar hypoplasia type 2E (PCH2E), characterized by microcephaly, severe neurodevelopmental impairment and epilepsy. We present a case of a female neonate with VP...Pathogenic variants in VPS53 are associated with pontocerebellar hypoplasia type 2E (PCH2E), characterized by microcephaly, severe neurodevelopmental impairment and epilepsy. We present a case of a female neonate with VPS53 pathogenic variants exhibiting the classic phenotypic features along with liver disease and deafness, which had not been described in previously reported cases. Similarly, while liver abnormalities have been reported in patients with mutations in other genes coding for proteins of the GARP or EARP complex, of which VPS53 is a subunit, liver disease has not been described in PCH2E until now. This case suggests that liver involvement may be an under-recognized feature of PCH2E and, more broadly, in GARP or EARP dysfunction, warranting further investigation.
Rare and undiagnosed diseases collectively represent a global health priority, presenting distinct challenges for healthcare systems due to their low prevalence, cumulative frequency, and complex care requirements. The i...Rare and undiagnosed diseases collectively represent a global health priority, presenting distinct challenges for healthcare systems due to their low prevalence, cumulative frequency, and complex care requirements. The impact of rare and undiagnosed diseases on children and their families extends beyond physical and mental health, affecting every aspect of their lives. This paper outlines the development of an innovative Model of Care that emphasises cross-sector care coordination as an approach to enhance the health and wellbeing of Western Australian children living with rare and undiagnosed diseases. Detailing insights gained will support and guide healthcare professionals to create services that improve outcomes for people living with rare diseases and undiagnosed diseases and their families.
Osman K, Asaly A, Halloun R
… +5 more, Paperna T, Pollack S, Magen D, Tiosano D, Weiss K
Eur J Med Genet
· 2025 Feb · PMID 39788453
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BACKGROUND: Ulnar mammary syndrome (UMS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in the T-box transcription factor 3 (TBX3) gene. The phenotype is classically characterized by upper l...BACKGROUND: Ulnar mammary syndrome (UMS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in the T-box transcription factor 3 (TBX3) gene. The phenotype is classically characterized by upper limb defects and apocrine/mammary gland hypoplasia. Endocrine abnormalities include hypogonadotropic hypogonadism (HH), partial growth hormone deficiency and dysmorphic features, while ectopic pituitary gland and various congenital anomalies have also been described. Here, we report a family with a unique clinical presentation. METHODS: Exome sequencing was performed for twin siblings with micropenis, neonatal hypogonadism, and congenital giant bladder diverticula. RESULTS: We identified a novel likely pathogenic heterozygous TBX3 variant c.844G>T; p.(Gly282Cys) inherited from the apparently unaffected mother. Reverse phenotyping confirmed that the mother and the twins had features suggestive of UMS spectrum. The mother had been diagnosed as having HH, with an hypoplastic pituitary gland. The physical examination revealed a bifid nasal tip and a bi-lobulated tongue tip typical for UMS with no apparent limb or mammary defects. DISCUSSION: This report extends the phenotype of the TBX3-related disorder to include HH and bladder anomalies without significant limb or mammary manifestations.
Watanabe D, Hasebe Y, Yagasaki H
… +11 more, Nakato D, Yamada M, Suzuki H, Kono Y, Sunaga Y, Yoshizawa M, Narusawa H, Miya F, Takenouchi T, Inukai T, Kosaki K
Eur J Med Genet
· 2025 Feb · PMID 39740729
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Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED ha...Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED have been described. Calcifications were present in three patients with CHDED. (two patients; renal calcifications, one patient; brain calcifications). The organ distribution of calcifications in CHDED has been unclear. We report here another patient with CHDED and brain calcifications. The patient was a 9-month-old Japanese girl. She presented with heart defects and ectodermal dysplasia. At 6 months of age, she had generalized seizures, and a CT scan revealed calcifications in the bilateral deep cerebral white matter. The seizures resolved with the administration of levetiracetam. The patient had a de novo, heterozygous pathogenic variant, c.1808G > A, p.(Arg603His), in the PRKD1 gene. Together with the previously reported patients mentioned above, we demonstrated the role of the PRKD1 variant in brain calcification. We propose that PRKD1 and two genes, ITGB2 and JAM2, which are known to be associated with brain calcification, act through a common signaling pathway abnormality. In support of our hypothesis, there are some experimental results that link PRKD1 and JAM2. PRKD1 functions with the integrin ITGB2 as a partner. JAM2, which is associated with brain calcification and is critical for maintaining of the tight junction of the endothelial cells, interacts with integrins including ITGB2. Therefore, PRKD1 could lead to the pathological phenotype of brain calcification.
Ringsted SB, Markholt S, Andreasen L
… +1 more, Gregersen PA
Eur J Med Genet
· 2025 Feb · PMID 39740728
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KAT6A syndrome or Arboleda-Tham Syndrome (ARTHS; OMIM #616268) is a syndromic neurodevelopmental disorder mainly presenting with variable degrees of intellectual disability (ID) and developmental delay (DD), especially s...KAT6A syndrome or Arboleda-Tham Syndrome (ARTHS; OMIM #616268) is a syndromic neurodevelopmental disorder mainly presenting with variable degrees of intellectual disability (ID) and developmental delay (DD), especially speech delay, hypotonia and autism spectrum disorders/behavioral problems. Multiple organ-systems including eyes, heart, gastrointestinal and neurological system can be involved. Other phenotypic features with a suggested association to KAT6A include immune dysfunction and pituitary anomalies. Initially, ID/DD was reported as universal in KAT6A syndrome; however, two children with normal assessment of intellect and development at age 10 and 11 years, were recently reported. KAT6A syndrome is caused by heterozygous pathogenic variants in KAT6A. Inherited variants are rare, and to our knowledge, only three inherited missense variants in KAT6A have been reported, whereas frameshift and nonsense variants have been inherited from mosaic parents only. Here, we report a Danish family, where an inherited KAT6A frameshift variant c.2710dup (p.(Glu904Glyfs∗12)) show clinical variability in disease phenotype expression among three family members. The description includes an affected first child with premature pubarche (the first individual to our knowledge), a mildly affected second child with normal cognitive performance assessment (the third reported individual with normal assessment of cognition and KAT6A syndrome), and a self-sufficient adult family member. The description expands the phenotypic spectrum of KAT6A syndrome, and thus brings important knowledge for improved management and counselling of patients and families with this rare condition.
Chen J, Li XP, Luo GJ
… +4 more, Yu XM, Liu QY, Peng M, Hou M
Eur J Med Genet
· 2025 Feb · PMID 39709006
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Lissencephaly (LIS) is a subtype of malformations of cortical development (MCD), characterized by smooth brain surfaces and underdeveloped gyri and sulci. This study investigates the genetic cause of pachygyria in a Chin...Lissencephaly (LIS) is a subtype of malformations of cortical development (MCD), characterized by smooth brain surfaces and underdeveloped gyri and sulci. This study investigates the genetic cause of pachygyria in a Chinese male infant diagnosed with the condition, who previously showed no causative variant through trio whole exome sequencing (Trio-WES) and copy number variation sequencing (CNVseq). Whole-genome sequencing (WGS) was conducted, revealing a novel heterozygous inversion spanning 1.02M bps on chromosome 17 [seq[GRCh37]inv(17)(p13.3p13.2)|NC_000017.10:g.2562761_3581978inv] involving the PAFAH1B1 gene. This de novo variant, confirmed by PCR and Sanger sequencing, was present in the proband but absent in the parents. The inversion disrupts PAFAH1B1, classified as haploinsufficient in the ClinGen database, and is associated with lissencephaly-1 (LIS1) and subcortical band heterotopia (SBH) (OMIM #607432). The findings align with the known characteristics of this disorder, extending the understanding of the molecular mechanisms underlying pachygyria. This identification offers new insights for individuals with developmental delays and brain malformations to uncover the genetic cause of their conditions.
Eur J Med Genet
· 2025 Feb · PMID 39709005
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The Chromodomain Helicase DNA-binding (CHD) protein family is ATP-dependent chromatin remodeling proteins that utilize energy produced by ATP hydrolysis to regulate chromatin structure and thereby modulate gene expressio...The Chromodomain Helicase DNA-binding (CHD) protein family is ATP-dependent chromatin remodeling proteins that utilize energy produced by ATP hydrolysis to regulate chromatin structure and thereby modulate gene expression. The earliest report of a CHD3 gene mutation was by O'Roak, who found it during whole exome sequencing of 189 autism families in 2012. In 2018, Snijders Blok systematically assessed the autosomal dominant neurodevelopmental disorder caused by CHD3 gene damage, known as Snijders Blok-Campeau syndrome (SNIBCPS, OMIM 618205). Its typical features include global developmental delay, speech delay, mild to severe intellectual disability, hypotonia, autism, and distinctive facial features such as macrocephaly (microcephaly in minority), prominent forehead and so on. This article reports a patient of slow speech, intellectual disability, epilepsy, spastic paraplegia, ataxia and situs inversus with a CHD3 gene mutation. The features of spastic paraplegia, ataxia, and situs inversus have not been reported previously. In conclusion, CHD3 gene mutations represent a rare disease with diverse clinical phenotypic features. This patient contributes valuable insights into the understanding of CHD3 gene mutation manifestations, expanding the scope beyond previously reported features.
Planté-Bordeneuve P, Boussion S, Caumes R
… +8 more, Rama M, Thuillier C, Boute-Benejean O, Vincent-Delorme C, Ait-Yahya E, Delobel B, Ghoumid J, Smol T
Eur J Med Genet
· 2025 Feb · PMID 39709004
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The X-linked NONO gene encodes Non-Pou Domain-Containing Octamer-Binding Protein, a multifunctional member of the DBHS family involved in transcriptional regulation, RNA splicing and DNA repair. Pathogenic variants in NO...The X-linked NONO gene encodes Non-Pou Domain-Containing Octamer-Binding Protein, a multifunctional member of the DBHS family involved in transcriptional regulation, RNA splicing and DNA repair. Pathogenic variants in NONO cause Intellectual Developmental Disorder, X-linked Syndromic (MIM #300967), characterised by intellectual disability, neurodevelopmental delay, cardiomyopathy, such as left ventricular non-compaction (LVNC), and congenital heart defects such as including atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), and patent foramen ovale (PFO). This study reports three new patients with pathogenic hemizygous frameshift variants in NONO identified with exome sequencing, broadening the clinical presentation. The patients present with neurodevelopmental delay, macrocephaly, agenesis or hypoplasia of the corpus callosum and LVNC, confirming previous findings. These findings contribute to the understanding of the phenotypic diversity in patients with NONO pathogenic variants and highlight the need for further investigation of genotype-phenotype correlations, particularly with regard to early cardiac development, and prenatal presentations.