Journal of Medical Genetics最新文献

{"title":"Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.","authors":"Kensuke Goto, Yoshito Koyanagi, Masato Akiyama, Yusuke Murakami, Masatoshi Fukushima, Kohta Fujiwara, Hanae Iijima, Mitsuyo Yamaguchi, Mikiko Endo, Kazuki Hashimoto, Masataka Ishizu, Toshiaki Hirakata, Kei Mizobuchi, Masakazu Takayama, Junya Ota, Ai Fujita Sajiki, Taro Kominami, Hiroaki Ushida, Kosuke Fujita, Hiroki Kaneko, Shinji Ueno, Takaaki Hayashi, Chikashi Terao, Yoshihiro Hotta, Akira Murakami, Kazuki Kuniyoshi, Shunji Kusaka, Yuko Wada, Toshiaki Abe, Toru Nakazawa, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Koji M Nishiguchi","doi":"10.1136/jmg-2023-109750","DOIUrl":"10.1136/jmg-2023-109750","url":null,"abstract":"<p><strong>Background: </strong>As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases.</p><p><strong>Methods: </strong>We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.</p><p><strong>Results: </strong>A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with <i>EYS</i> accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.</p><p><strong>Conclusion: </strong>A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"613-620"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ZFHX3</i> variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.","authors":"Ming-Feng He, Li-Hong Liu, Sheng Luo, Juan Wang, Jia-Jun Guo, Peng-Yu Wang, Qiong-Xiang Zhai, Su-Li He, Dong-Fang Zou, Xiao-Rong Liu, Bing-Mei Li, Hai-Yan Ma, Jing-Da Qiao, Peng Zhou, Na He, Yong-Hong Yi, Wei-Ping Liao","doi":"10.1136/jmg-2023-109725","DOIUrl":"10.1136/jmg-2023-109725","url":null,"abstract":"<p><strong>Background: </strong>The <i>ZFHX3</i> gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between <i>ZFHX3</i> variants and epilepsy.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A <i>Drosophila Zfh2</i> knockdown model was used to validate the association between <i>ZFHX3</i> and epilepsy.</p><p><strong>Results: </strong>Compound heterozygous <i>ZFHX3</i> variants were identified in eight unrelated cases. The burden of <i>ZFHX3</i> variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In <i>Zfh2</i> knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The <i>Zfh2</i> knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that <i>ZFHX3</i> orthologous were highly expressed in the embryonic stage and decreased dramatically after birth.</p><p><strong>Conclusion: </strong><i>ZFHX3</i> is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"652-660"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.","authors":"Terri Patricia McVeigh, Kevin J Monahan, Joseph Christopher, Nick West, Malcolm Scott, Jennie Murray, Helen Hanson","doi":"10.1136/jmg-2024-109886","DOIUrl":"10.1136/jmg-2024-109886","url":null,"abstract":"<p><strong>Background: </strong>Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR.</p><p><strong>Methods: </strong>This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance.</p><p><strong>Results: </strong>We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS.</p><p><strong>Conclusion: </strong>Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"707-715"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis.","authors":"Wen Wen, Zhengye Zhao, Zhifa Zheng, Sen Zhao, Hengqiang Zhao, Xi Cheng, Huakang Du, Ziquan Li, Shengru Wang, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Nan Wu","doi":"10.1136/jmg-2023-109667","DOIUrl":"10.1136/jmg-2023-109667","url":null,"abstract":"<p><strong>Background: </strong>Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear.</p><p><strong>Methods: </strong>Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation.</p><p><strong>Results: </strong><i>SLC16A8</i>, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious <i>SLC16A8</i> variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings.</p><p><strong>Conclusion: </strong>This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"666-676"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variants in Plexin B2 (<i>PLXNB2</i>) cause amelogenesis imperfecta, hearing loss and intellectual disability.","authors":"Claire E L Smith, Virginie Laugel-Haushalter, Ummey Hany, Sunayna Best, Rachel L Taylor, James A Poulter, Saskia B Wortmann, Rene G Feichtinger, Johannes A Mayr, Suhaila Al Bahlani, Georgios Nikolopoulos, Alice Rigby, Graeme C Black, Christopher M Watson, Sahar Mansour, Chris F Inglehearn, Alan J Mighell, Agnès Bloch-Zupan","doi":"10.1136/jmg-2023-109728","DOIUrl":"10.1136/jmg-2023-109728","url":null,"abstract":"<p><strong>Background: </strong>Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic <i>PLXND1</i> and <i>PLXNA1</i> variants have so far been associated with Mendelian genetic disease.</p><p><strong>Methods: </strong>Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.</p><p><strong>Results: </strong>Rare biallelic pathogenic variants in plexin B2 (<i>PLXNB2</i>), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. <i>Plxnb2</i> expression was detected in differentiating ameloblasts.</p><p><strong>Conclusion: </strong>We identify rare biallelic pathogenic variants in <i>PLXNB2</i> as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in <i>Plxnb2</i> knockout mice, and, together with the rarity of human <i>PLXNB2</i> variants, may explain why pathogenic variants in <i>PLXNB2</i> have not been reported previously.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"689-698"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>NASP</i> gene contributes to autism by epigenetic dysregulation of neural and immune pathways.","authors":"Sipeng Zhang, Jie Yang, Dandan Ji, Xinyi Meng, Chonggui Zhu, Gang Zheng, Joseph Glessner, Hui-Qi Qu, Yuechen Cui, Yichuan Liu, Wei Wang, Xiumei Li, Hao Zhang, Zhanjie Xiu, Yan Sun, Ling Sun, Jie Li, Hakon Hakonarson, Jin Li, Qianghua Xia","doi":"10.1136/jmg-2023-109385","DOIUrl":"10.1136/jmg-2023-109385","url":null,"abstract":"<p><strong>Background: </strong>Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology.</p><p><strong>Methods: </strong>Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene.</p><p><strong>Results: </strong>We identified a novel candidate gene <i>NASP</i> (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant t<i>NASP</i>(Q289X) subjects the expression of t<i>NASP</i> to nonsense-mediated decay. t<i>NASP</i> KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type t<i>NASP</i>, t<i>NASP</i>(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the t<i>NASP</i> mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in <i>Caenorhabditis elegans</i>. Two additional patients with ASD were found carrying deletion or deleterious mutation in the <i>NASP</i> gene.</p><p><strong>Conclusion: </strong>We identified novel epigenetic mechanisms mediated by t<i>NASP</i> which may contribute to the pathogenesis of ASD and its immune comorbidity.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"677-688"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survey of service needs to embed genome sequencing for motor neuron disease in neurology in the English National Health Service.","authors":"Jade Howard, Hilary L Bekker, Christopher J McDermott, Alisdair McNeill","doi":"10.1136/jmg-2023-109735","DOIUrl":"10.1136/jmg-2023-109735","url":null,"abstract":"<p><p>All people with motor neuron disease (pwMND) in England are eligible for genome sequencing (GS), with panel-based testing. With the advent of genetically targeted MND treatments, and increasing demand for GS, it is important that clinicians have the knowledge and skills to support pwMND in making informed decisions around GS. We undertook an online survey of clinical genomic knowledge and genetic counselling skills in English clinicians who see pwMND. There were 245 respondents to the survey (160 neurology clinicians and 85 genetic clinicians). Neurology clinicians reported multiple, overlapping barriers to offering pwMND GS. Lack of time to discuss GS in clinic and lack of training in genetics were reported. Neurology clinicians scored significantly less well on self-rated genomic knowledge and genetic counselling skills than genetic clinicians. The majority of neurology clinicians reported that they do not have adequate educational or patient information resources to support GS discussions. We identify low levels of genomic knowledge and skills in the neurology workforce. This may impede access to GS and precision medicine for pwMND.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"661-665"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Encephalocraniocutaneous lipomatosis phenotype associated with mosaic biallelic pathogenic variants in the NF1 gene","authors":"Steven Smeijers, Hilde Brems, Alexander Verhaeghe, Wim van Paesschen, Johannes van Loon, Seppe Van der Auweraer, Raf Sciot, Dietmar Rudolf Thal, Lieven Lagae, Eric Legius, Tom Theys","doi":"10.1136/jmg-2023-109785","DOIUrl":"https://doi.org/10.1136/jmg-2023-109785","url":null,"abstract":"Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second-hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second-hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second-hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS-MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS-MAPK pathway.","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"47 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141190490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals.","authors":"Lottie D Morison, Milou G P Kennis, Dmitrijs Rots, Arianne Bouman, Joost Kummeling, Elizabeth Palmer, Adam P Vogel, Frederique Liegeois, Amanda Brignell, Siddharth Srivastava, Zoe Frazier, Di Milnes, Himanshu Goel, David J Amor, Ingrid E Scheffer, Tjitske Kleefstra, Angela T Morgan","doi":"10.1136/jmg-2023-109702","DOIUrl":"10.1136/jmg-2023-109702","url":null,"abstract":"<p><strong>Objectives: </strong>Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome.</p><p><strong>Method: </strong>103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained.</p><p><strong>Results: </strong>The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression.</p><p><strong>Conclusions: </strong>The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"578-585"},"PeriodicalIF":4.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.","authors":"Didier Lacombe, Agnès Bloch-Zupan, Cecilie Bredrup, Edward B Cooper, Sofia Douzgou Houge, Sixto García-Miñaúr, Hülya Kayserili, Lidia Larizza, Vanesa Lopez Gonzalez, Leonie A Menke, Donatella Milani, Francesco Saettini, Cathy A Stevens, Lloyd Tooke, Jill A Van der Zee, Maria M Van Genderen, Julien Van-Gils, Jane Waite, Jean-Louis Adrien, Oliver Bartsch, Pierre Bitoun, Antonia H M Bouts, Anna M Cueto-González, Elena Dominguez-Garrido, Floor A Duijkers, Patricia Fergelot, Elizabeth Halstead, Sylvia A Huisman, Camilla Meossi, Jo Mullins, Sarah M Nikkel, Chris Oliver, Elisabetta Prada, Alessandra Rei, Ilka Riddle, Cristina Rodriguez-Fonseca, Rebecca Rodríguez Pena, Janet Russell, Alicia Saba, Fernando Santos-Simarro, Brittany N Simpson, David F Smith, Markus F Stevens, Katalin Szakszon, Emmanuelle Taupiac, Nadia Totaro, Irene Valenzuena Palafoll, Daniëlle C M Van Der Kaay, Michiel P Van Wijk, Klea Vyshka, Susan Wiley, Raoul C Hennekam","doi":"10.1136/jmg-2023-109438","DOIUrl":"10.1136/jmg-2023-109438","url":null,"abstract":"<p><p>Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (<i>CREBBP</i>, <i>EP300</i>) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: <i>CREBBP</i>; RTS2: <i>EP300</i>), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"503-519"},"PeriodicalIF":4.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}