European journal of medical genetics最新文献

{"title":"Hepatic manifestations in VPS53-related pontocerebellar hypoplasia type 2E: a case report.","authors":"Auriane Mouchez, Célia Hoebeke, Béatrice Desnous, Aline Cano, Radia Fritih, Alexandre Fabre","doi":"10.1016/j.ejmg.2025.104996","DOIUrl":"https://doi.org/10.1016/j.ejmg.2025.104996","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104996"},"PeriodicalIF":1.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare Care - Cross-Sector Care Coordination.","authors":"Gareth Baynam, Joanne Siffleet, Theresa Abbott, Sue Baker, Daniella Dye, Amanda Newell, Stephanie Broley, Kaila Stevens","doi":"10.1016/j.ejmg.2025.104995","DOIUrl":"https://doi.org/10.1016/j.ejmg.2025.104995","url":null,"abstract":"<p><p>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 well-being 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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104995"},"PeriodicalIF":1.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A family with an atypical presentation of TBX3-related disorder.","authors":"Khaled Osman, Ayman Asaly, Rana Halloun, Tamar Paperna, Shirley Pollack, Daniella Magen, Dov Tiosano, Karin Weiss","doi":"10.1016/j.ejmg.2025.104994","DOIUrl":"10.1016/j.ejmg.2025.104994","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Exome sequencing was performed for twin siblings with micropenis, neonatal hypogonadism, and congenital giant bladder diverticula.</p><p><strong>Results: </strong>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.</p><p><strong>Discussion: </strong>This report extends the phenotype of the TBX3-related disorder to include HH and bladder anomalies without significant limb or mammary manifestations.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104994"},"PeriodicalIF":1.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain calcification in congenital heart defects and ectodermal dysplasia (CHDED).","authors":"Daisuke Watanabe, Yohei Hasebe, Hideaki Yagasaki, Daisuke Nakato, Mamiko Yamada, Hisato Suzuki, Yosuke Kono, Yuto Sunaga, Masashi Yoshizawa, Hiromune Narusawa, Fuyuki Miya, Toshiki Takenouchi, Takeshi Inukai, Kenjiro Kosaki","doi":"10.1016/j.ejmg.2024.104992","DOIUrl":"10.1016/j.ejmg.2024.104992","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104992"},"PeriodicalIF":1.6,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic variability in a family with an inherited KAT6A frameshift variant.","authors":"Sidsel Bjerg Ringsted, Sara Markholt, Lotte Andreasen, Pernille Axél Gregersen","doi":"10.1016/j.ejmg.2024.104993","DOIUrl":"10.1016/j.ejmg.2024.104993","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104993"},"PeriodicalIF":1.6,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CHD3-related Snijders Blok-Campeau syndrome with Spastic Paraplegia, Ataxia, and Situs Inversus.","authors":"Lin Chen, Yanjiao Bu, Yuwen Yu, Yongxing Chen, Xiaoguang Lei","doi":"10.1016/j.ejmg.2024.104988","DOIUrl":"10.1016/j.ejmg.2024.104988","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104988"},"PeriodicalIF":1.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalogue of inherited autosomal recessive disorders found amongst the Roma population of Europe.","authors":"Shauna Quinn, Nicola Walsh, Ioana Streata, Athina Ververi, Samarth Kulshrestha, Ratna Dua Puri, Anca Lelia Riza, Aoibhinn Walsh, Kathleen Gorman, Ellen Crushell, Andrew Green, Janna Kenny, Sally Ann Lynch","doi":"10.1016/j.ejmg.2024.104989","DOIUrl":"10.1016/j.ejmg.2024.104989","url":null,"abstract":"<p><strong>Background: </strong>The Roma population are an endogamous, genetically isolated, minority population who migrated from North-Western India to Europe from the 10th Century throughout the Byzantine period and continues to the present day. Approximately 10-12 million Romani people reside in segregated settlements in Europe, and smaller populations live in North America and China. In addition to the endogamy, they also practice consanguinity. This has resulted in a higher frequency of rare autosomal recessive disorders some of which are unique to the Roma population. Some disorders result from founder variants whilst others are private variants, occurring within one nuclear family. Most are found as homozygous variants but compound heterozygosity is seen in a number of conditions.</p><p><strong>Objective: </strong>Clinicians and scientists with experience in managing and diagnosing rare diseases in this population in Ireland, Romania and Greece have developed a comprehensive catalogue of autosomal recessive inherited disorders found in the Roma population. Our aim is that this catalogue will aid rapid diagnosis and highlight the differential diagnoses to consider in challenging cases.</p><p><strong>Methods: </strong>We performed a detailed literature search to identify relevant publications and disease variants described in patients whose ethnicity was described as Roma. In addition, we interrogated data from local clinicians and colleagues in Ireland and Romania to collect additional unpublished variants which have yet to be reported in the medical literature. Where possible, we have mapped these disorders back to their European country of origin. Furthermore, we searched the variants allele frequencies on ClinVar. We analysed exome data from New Delhi, India to trace any of these founder variants back their origins.</p><p><strong>Results: </strong>We identified 90 distinct autosomal recessive disorders, manifesting as 91 distinct phenotypes and 111 pathogenic disease variants. These include both published (n = 91) and unpublished (n = 20) findings identified in the Roma population in Europe. The Indian exome data revealed that only 12/111 variants were identified.</p><p><strong>Conclusion: </strong>We have assembled a catalogue of inherited autosomal recessive disorders and 111 pathogenic variants found in the Roma population. We hope that this will assist the medical and scientific community to make prompt diagnoses and consider adaptation of a targeted genetic approach to facilitate timely and cost-effective diagnoses in this population.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104989"},"PeriodicalIF":1.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort.","authors":"Davide Vecchio, Filippo M Panfili, Marina Macchiaiolo, Maria Lisa Dentici, Marina Trivisano, Carolina Benitez Medina, Rossella Capolino, Emanuela Salzano, Fabiana Cortellessa, Martina Busè, Antonio Pantaleo, Dario Cocciadiferro, Michaela V Gonfiantini, Marcello Niceta, Angela De Dominicis, Nicola Specchio, Maria Piccione, Maria Cristina Digilio, Marco Tartaglia, Antonio Novelli, Andrea Bartuli","doi":"10.1016/j.ejmg.2024.104990","DOIUrl":"10.1016/j.ejmg.2024.104990","url":null,"abstract":"<p><p>O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestations. It is caused by pathogenic variants in the KMT2E gene. Here we report seven new patients with loss-of-function KMT2E variants, six harboring frameshift/nonsense changes, and one with a 7q22.3 microdeletion encompassing the entire gene-locus. We further characterize both the clinical phenotype as well as its associated pathogenic variants' spectrum providing new information on sex-related phenotype distribution, according to the variant groups. We also highlight different epilepsy phenotype-genotype correlation with preferential association of generalized epilepsy and/or developmental and epileptic encephalopathy with missense pathogenic variants and focal epilepsy, childhood absence epilepsy and/or febrile seizures with pathogenic truncating variants and structural rearrangements. By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104990"},"PeriodicalIF":1.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous inversion on chromosome 17 involving PAFAH1B1 detected by whole genome sequencing in a patient suffering from pachygyria.","authors":"Jun Chen, Xiao-Ping Li, Guang-Jin Luo, Xiao-Ming Yu, Qiu-Yan Liu, Min Peng, Mei Hou","doi":"10.1016/j.ejmg.2024.104991","DOIUrl":"10.1016/j.ejmg.2024.104991","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104991"},"PeriodicalIF":1.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NONO-related X-linked intellectual disability syndrome: Further clinical and molecular delineation.","authors":"Pauline Planté-Bordeneuve, Simon Boussion, Roseline Caumes, Mélanie Rama, Caroline Thuillier, Odile Boute-Benejean, Catherine Vincent-Delorme, Emilie Ait-Yahya, Bruno Delobel, Jamal Ghoumid, Thomas Smol","doi":"10.1016/j.ejmg.2024.104987","DOIUrl":"10.1016/j.ejmg.2024.104987","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"104987"},"PeriodicalIF":1.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}