European journal of medical genetics最新文献

{"title":"Autosomal recessive frameshift variant broadens HECW2-related disease spectrum","authors":"Reyhaneh Dehghanzad ,&nbsp;Yeganeh Eshaghkhani ,&nbsp;Mohammad Saberi ,&nbsp;Maryam Jamshidifar ,&nbsp;Parvaneh Karimzadeh ,&nbsp;Mohammad Keramatipour","doi":"10.1016/j.ejmg.2025.105036","DOIUrl":"10.1016/j.ejmg.2025.105036","url":null,"abstract":"<div><div>The <em>HECW2</em> gene encodes a HECT (homologous to E6-AP carboxy terminus)-type E3 ubiquitin ligase that plays a critical role in neurodevelopment. Pathogenic variants in <em>HECW2</em> are associated with a neurodevelopmental disorder characterized by hypotonia, seizures, and absent language (NDHSAL; OMIM #617268), typically inherited in an autosomal dominant pattern. However, recent evidence suggests that some variants in <em>HECW2</em> gene may cause the disease with autosomal recessive inheritance.</div><div>Here, we report a 6-year-old female proband of consanguineous Afghan descent who presented with severe microcephaly, hypotonia, failure to thrive, recurrent seizures, global neurodevelopmental delay, and brain MRI findings of significant cerebral and cerebellar atrophy. Whole-exome sequencing revealed a novel homozygous frameshift variant in <em>HECW2</em> (c.3601_3602insT, p.Y1201Lfs∗7, ClinVar: SCV006279594) in this patient. In silico analyses and Sanger validation confirmed the pathogenicity of this variant and its autosomal recessive inheritance, with both parents being heterozygous carriers but clinically unaffected. This frameshift variant likely results in nonsense-mediated decay (NMD) of the mRNA, suggesting a loss-of-function mechanism distinct from the mechanism implicated in missense variants that causing the disease with autosomal dominant inheritance.</div><div>This study expands the phenotype and genetic spectrum of <em>HECW2</em>-related disorders and highlights the importance of recognizing autosomal recessive inheritance patterns. The findings emphasize the need for comprehensive genetic analyses, especially in consanguineous populations, and underscore the value of considering null variants in HECW2 when evaluating severe neurodevelopmental phenotypes. Further studies exploring the molecular mechanisms of <em>HECW2</em> variants are essential to deepen our understanding of its role in neurodevelopment and refine diagnostic and therapeutic approaches.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"77 ","pages":"Article 105036"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842465","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":"Aminoacyl-tRNA synthetase: A ‘semiotic enzyme’","authors":"Praveen Prathapan","doi":"10.1016/j.ejmg.2025.105041","DOIUrl":"10.1016/j.ejmg.2025.105041","url":null,"abstract":"<div><div>The genetic code is the set of rules by which nucleotide sequences correspond to amino acids. These rules are enforced by aminoacyl-tRNA synthetases (aaRSs): enzymes that ligate amino acids to tRNA molecules. Here it is argued this reaction suggests the genetic code may be understood as a ‘code process’. Contrary to the prevailing adaptor model of the genetic code based on tRNAs, the semiotic model recognises a ‘genetic code process’ catalysed by aaRSs.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"77 ","pages":"Article 105041"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894898","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":"Poorly described phenotypes add to the misfortune of rare diseases.","authors":"Fabre A, Aouchiche K, Reynaud R","doi":"10.1016/j.ejmg.2025.105034","DOIUrl":"10.1016/j.ejmg.2025.105034","url":null,"abstract":"<p><p>An often overlooked problem in the characterization of rare diseases is the contingent and evolving nature of accepted phenotypes. In the era of next-generation sequencing and genotype-first approaches to patient care, we illustrate the pitfalls of superficial phenotype descriptions via a historic overview of Alagille syndrome. These reflections lead us to a series of recommendations to improve phenotype descriptions, namely to encourage and standardize case reports and create case databases including follow-up data.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105034"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811961","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":"Further delineation of LRSAM1-related Charcot-Marie-Tooth type 2P with parkinsonism.","authors":"Pauline Ducatel, Antoine Verger, Marion Selton, Mathilde Renaud, Salome Puisieux, Anais Grosset, Lucie Hopes, Maud Michaud","doi":"10.1016/j.ejmg.2025.105032","DOIUrl":"10.1016/j.ejmg.2025.105032","url":null,"abstract":"<p><p>LRSAM1 pathogenic variations are linked to an axonal motor and sensory polyneuropathy known as Charcot-Marie-Tooth disease type 2P, but extra peripheral neurologic impairment is suspected. We report a patient with CMT2P and parkinsonism. We describe a 66-year-old man presenting with pes cavus, gait instability, and mild distal motor weakness. Nerve conduction studies revealed sensory-motor axonal neuropathy consistent with CMT2P. After several months, he developed lower-limb and right upper-limb hypertonia, jerky eyes, and hypomimia. ¹²³ I-FP-CIT single-photon emission computed tomography revealed bilateral alteration of the presynaptic dopaminergic pathway, especially regarding the putamen. The full CMT panel confirmed a heterozygote pathogenic variant (NM_001005373.4: c.2093_2104del, p.(Gln698_Gln701del)) in the LRSAM1 gene. To the best of our knowledge, this is the seventh clinical description linking an LRSAM1 pathogenic variant and parkinsonism. Consequently, we believe that patients with parkinsonism and sensorimotor axonal neuropathy should be explored for LRSAM1 mutation.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105032"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728981","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":"Vascular findings in five unrelated children with vascular Ehlers-Danlos syndrome: A multi-case report","authors":"Anna Irene Skei Sekkelsten ,&nbsp;Thor Håkon Skattør ,&nbsp;Henrik Holmstrøm ,&nbsp;Kirsten Krohg-Sørensen ,&nbsp;Benedicte Paus","doi":"10.1016/j.ejmg.2025.105035","DOIUrl":"10.1016/j.ejmg.2025.105035","url":null,"abstract":"<div><div>Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder caused by heterozygous variants in <em>COL3A1</em>, leading to tissue and vessel fragility alongside an increased risk of potentially fatal aneurysms and dissections. Although vascular events most commonly manifest in adulthood, childhood events also occur. Knowledge on clinical manifestations in childhood and potential benefits of vascular surveillance is limited, and no evidence-based guidelines for predictive genetic testing and follow-up exist.</div><div>We present five patients diagnosed with vEDS in childhood, focusing on vascular events. The patients receive follow-up at a multidisciplinary heritable thoracic aortic disease clinic at Oslo University Hospital and are registered in the associated patient registry.</div><div>Two of the five patients experienced a childhood vascular event, both involving cerebral vessels. In one of these patients, the event may not be vEDS related. A mild aortic root dilatation was detected in one patient. No severe aortic events like dissection or rupture were reported in childhood, but one patient died from an aortic dissection in early adulthood despite normal findings on MRA scans in the years he received regular surveillance.</div><div>Our findings highlight the variable expressivity of vEDS, including severe childhood vascular events. Further studies to evaluate the effect of surveillance are needed to form an evidence base for surveillance guidelines in pediatric patients. Established benefits of surveillance and management are essential for deciding on whether and when to perform predictive genetic testing of a child at risk.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"77 ","pages":"Article 105035"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854961","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":"Overview and expansion of CEP85L-associated lissencephaly","authors":"Isabell Schumann ,&nbsp;Rami Abou Jamra ,&nbsp;Robin-Tobias Jauss ,&nbsp;Maike Karnstedt ,&nbsp;Ulrich Specht ,&nbsp;Pia Zacher ,&nbsp;Friedrich Woermann ,&nbsp;Yuval Yaron ,&nbsp;Bernt Popp","doi":"10.1016/j.ejmg.2025.105042","DOIUrl":"10.1016/j.ejmg.2025.105042","url":null,"abstract":"<div><div>Defective neuronal migration causes lissencephaly (LIS), a neurodevelopmental disorder (NDD) with a smooth cerebral surface and abnormal cortical thickness. Variants in <em>CEP85L</em> are linked to posterior predominant LIS, but the phenotype and genotype are unclear. Three new unrelated cases of <em>CEP85L</em>-associated LIS are presented, including the first prenatal diagnosis and a mosaic variant. Clinical, neuroimaging, and genetic analyses were recorded. Data from 29 previously reported individuals was used in a comprehensive literature review. Human phenotype ontology (HPO) terms were used to annotate phenotypic features, and American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate variants. All postnatal individuals had variable NDD. Global developmental delay was observed in 71 % (22/31), speech or motor delay in 54 % (11/31 and 6/31, respectively), and intellectual disability in 74 % (23/31) of cases. Focused and generalized-onset seizures occurred in 90 % (28/31). Brain magnetic resonance imaging (MRI) revealed predominantly posteriorly predominant LIS in all evaluated individuals, with 55 % (17/31) of cases also exhibiting subcortical band heterotopia (SBH). A total of 18 different <em>CEP85L</em> variants were identified among all individuals, all clustering in a highly conserved N-terminal region between amino acids 1 and 103. These included 10 missense mutations, five splice-site alterations, two start-loss variants, and one stop variant. Nine <em>de novo</em> variants, 10 mother-father variants, and 13 variants with unknown inheritance. Genotype-phenotype correlations in <em>CEP85L</em>-associated LIS show that stronger splice and germline variants often cause more severe symptoms than mosaic variants. To reduce confusion caused by alternative <em>CEP85L</em> transcripts, we recommend NM_001042475 for variant interpretation. These findings improve this disorder's genetic diagnostics and counseling framework.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"77 ","pages":"Article 105042"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947187","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":"Parental experiences and needs in Kleefstra Syndrome: A semi-structured interview study","authors":"Sietske A.L. van Till ,&nbsp;Arianne Bouman ,&nbsp;Tjitske Kleefstra ,&nbsp;Eline M. Bunnik","doi":"10.1016/j.ejmg.2025.105037","DOIUrl":"10.1016/j.ejmg.2025.105037","url":null,"abstract":"<div><div>Kleefstra Syndrome (KLEFS1) is a monogenic neurodevelopmental disorder characterized by developmental delays, somatic issues, and (neuro)psychiatric symptoms. Individuals with KLEFS1 often require complex, ongoing support, which significantly impacts family life. To effectively improve care and support for families, a better understanding is needed of the impacts of raising a child with KLEFS1 on the family and families' support needs. We conducted a semi-structured interview study among parents of children with KLEFS1 to investigate these impacts. The interviews were audio-recorded, transcribed, coded, and thematically analyzed. We conducted 12 interviews with 15 parents of children with KLEFS1 (8–25 years old), in the Netherlands and Belgium. Over the years, parents have encountered significant challenges. Although parents value timely diagnosis, the emotional impact was profound, especially for parents of younger children. Parents focused on their children's developmental symptoms, and behavioral and psychiatric symptoms, which had significant impacts, including impacts on parents' employment status, their ability to undertake activities, and emotional well-being. Parents were concerned about their children's future, because of children's lifelong dependency and risk of regression. Parents prioritized receiving adequate care and support to decrease the burden on their family and to improve their child's well-being. To better support families, the accessibility of social support needs to be improved, e.g., by expanding respite care services and specialized schooling, simplifying regulations for accessing social support, and providing tailored emotional support and information during the diagnostic process. When developing treatments, researchers should incorporate parental experiences in defining patient-relevant outcome measures.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"77 ","pages":"Article 105037"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882484","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 fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST","authors":"Dominique Braun ,&nbsp;Sofia Amylidi-Mohr ,&nbsp;Olaf Ahrens ,&nbsp;Mafalda Trippel ,&nbsp;Rike Schiller ,&nbsp;Christiane Zweier","doi":"10.1016/j.ejmg.2025.105040","DOIUrl":"10.1016/j.ejmg.2025.105040","url":null,"abstract":"<div><div>Stüve-Wiedemann syndrome is a rare skeletal dysplasia characterized by severe shortening and bowing of the long bones and by immunological and autonomous dysfunction, usually resulting in early death. Bi-allelic loss-of-function variants in either the leukemia inhibitory factor receptor encoding <em>LIFR</em> or the interleukin-6 cytokine family signal transducer encoding <em>IL6ST</em> are causative. So far, five individuals from three unrelated families were described with <em>IL6ST</em> associated Stüve-Wiedemann syndrome. We here report on a sixth case that came to attention at 21 weeks of gestation with short and bowed long bones. Prenatal trio exome sequencing revealed the homozygous novel variant p.(Ser375∗) in <em>IL6ST</em> in the fetus. The further course of the pregnancy was complicated by early rupture of the membranes and preeclampsia. The fetus died <em>in utero</em> in gestational week 34 and was born with dolichocephalus, severe bowing and shortening of limb bones, a narrow upper thorax, joint dislocations and abnormal bone mineralization.</div><div>With this case report, we further delineate the molecular and clinical spectrum of <em>IL6ST</em> related Stüve-Wiedemann syndrome.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"77 ","pages":"Article 105040"},"PeriodicalIF":1.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878405","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":"Parental communication about inherited conditions with young Children: Insights from genetic professionals in Portugal","authors":"Catarina Seidi ,&nbsp;Liliana Sousa ,&nbsp;Álvaro Mendes","doi":"10.1016/j.ejmg.2025.105025","DOIUrl":"10.1016/j.ejmg.2025.105025","url":null,"abstract":"<div><div>Genetic healthcare professionals (GHP) are key in supporting parents in communicating about inherited genetic conditions (IGC) with their young children. This study explored the attitudes, clinical practice and perceptions of Portuguese GHP’ regarding parental communication about IGC with young children. We conducted an observational and cross-sectional study with 32 GHP, 75 % of whom were women, and 37.5 % were aged 31–40 years old. The survey included sociodemographic and professional questions, along with 35 statements to be answered on a 4-point Likert scale (ranging from 1- strongly disagree to 4- strongly agree). Key findings show that GHP: (i) perceive that parents fear the impact of genetic information on their children's emotional wellbeing (3.53 ± 0.51), are receptive to support from GHP (3.16 ± 0.57), and should tailor communication to children's developmental stage (3.56 ± 0.50); (ii) report being available to support parents when asked (3.56 ± 0.62) and encourage parents to communicate openly (3.47 ± 0.57); and (iii) assess parents' level of understanding about the IGC (3.41 ± 0.56), raise parents' awareness of the importance of informing their children (3.28 ± 0.52), and support parents in adapting communication to the type of IGC (3.28 ± 0.58), and the child's developmental stage (3.22 ± 0.55). Results emphasize critical role of GHP in facilitating parent-child communication about IGC, highlighting their commitment to supporting these sensitive conversations.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"76 ","pages":"Article 105025"},"PeriodicalIF":1.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233600","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 novel RORA genetic variant associated with early-onset obesity and insomnia","authors":"Alexie Ouellette ,&nbsp;Eric P. Allain ,&nbsp;Abdullah Almaghraby ,&nbsp;Dominique Bouhamdani ,&nbsp;Mouna Ben Amor","doi":"10.1016/j.ejmg.2025.105028","DOIUrl":"10.1016/j.ejmg.2025.105028","url":null,"abstract":"<div><div>Retinoic acid-related orphan receptor alpha (<em>RORA</em>) pathogenic variants cause intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA). Herein, we present a female patient with a novel heterozygous likely pathogenic <em>RORA</em> variant, c.484C &gt; T p.(Arg162∗), with a clinical manifestation overlapping IDDECA. The patient also presented previously undocumented symptoms, namely, early-onset obesity and insomnia. Furthermore, parental testing revealed inheritance from the mother who presented a congruent phenotype. This suggests a role for <em>RORA</em> in both sleep and metabolism whilst extending the phenotypic spectrum of IDDECA. Notwithstanding, more fundamental work is needed to delineate the role of <em>RORA</em> variants in disease.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"76 ","pages":"Article 105028"},"PeriodicalIF":1.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293572","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}