European journal of medical genetics最新文献

{"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":"Cost-comparison of resequencing versus archival data methods for periodic reanalysis of genomic data in rare diseases diagnosis: A UK pilot analysis","authors":"Ravi Prabhakar More ,&nbsp;Dulika Sumathipala ,&nbsp;Helen Dolling ,&nbsp;Kate Downes ,&nbsp;Sarah Bowdin ,&nbsp;Joowook Ahn ,&nbsp;Stephen Morris ,&nbsp;David H. Rowitch","doi":"10.1016/j.ejmg.2025.105051","DOIUrl":"10.1016/j.ejmg.2025.105051","url":null,"abstract":"<div><div>Periodic reanalysis of genome sequence data in rare diseases to improve diagnostic rates is recommended every 18-months. However, cost can be a major consideration. We compared the cost of two reanalysis methods: (A) resequencing of stored DNA and (B) archived genome data. We selected 30 trios with diverse molecular diagnoses for reanalysis from the published Next Generation Children Project (NGC), which used whole genome sequencing (WGS) on a paediatric cohort from NICU/PICU. Of these, 29 trio samples passed the DNA QC, were re-sequenced (Method A), or their initial sequence data retrieved from archival (Method B) prior to gene diagnostic analysis. Both Methods A and B detected 100 % (41/41) of the known diagnostic variants, with assessors blinded to previous findings. We performed cost comparisons per trio and UK NHS rare diseases (NICU/PICU) cohort national scale including analysis and data storage costs. While re-sequenced WGS data showed a higher quality of Q30 reads (median 89.9 %) as compared to archived data (median 86.54 %), the cost per trio was £5021.17 and £2136.96, respectively (difference of £2884.21). Extrapolating to a national UK paediatric intensive care cohort (∼90K admissions per annum) with gene agnostic analysis, Method B yields significant cost savings, even with only one reanalysis. Periodic WGS reanalysis using archival data is as accurate as resequencing at a lesser cost per trio but at scale this requires federated archival data repositories.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105051"},"PeriodicalIF":1.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206000","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 features in Feingold syndrome type 1.","authors":"Fanny Ferroul, Sarah Snanoudj, Gaëlle Leterme, Kheira Mezouaghi, Marie Kieffer-Traversier, Tristan Celse, Jessica Dospeux, Thomas Huby, Pauline Marzin, Godelieve Morel, Frédérique Payet, Mathilde Remy, Laetitia Sennsfelder, Marta Spondenkiewicz, Bérénice Roy-Doray, Jeanne Amiel, Veronique Pingault, Jean-Luc Alessandri","doi":"10.1016/j.ejmg.2025.105049","DOIUrl":"https://doi.org/10.1016/j.ejmg.2025.105049","url":null,"abstract":"<p><p>Feingold syndrome type 1 (FS1) (OMIM 164280) is an autosomal dominant condition due to heterozygous loss of function variants in MYCN gene or to 2p24 deletion encompassing MYCN gene. The core features of FS1 are digital anomalies, microcephaly, facial dysmorphism, short stature, esophageal/duodenal atresia, and mild learning disabilities. Additional features are reported in a minority of patients, such as cardiac and renal anomalies. Sensorineural deafness is reported in 7 % of the patients. Other features can be associated with classical features of FS1 in patients with 2p deletion including MYCN and other genes. Recently, absence of the flexor pollicis longus tendon has been reported as a new skeletal feature in a pedigree segregating a MYCN variant. Here, we reported on three patients having FS1 without gastrointestinal atresia and unusual features: laryngeal cleft, congenital deafness, agenesis of the corpus callosum, and radio ulnar-synostosis (RUS). After the extension of the genetic screening, RUS was considered as an independent condition linked to SMAD6 variant. Diagnosis of FS1 can be challenging when there are unusual features without digestive malformations drawing attention. In this situation, the diagnostic approach may be based on major criteria of FS1: i) brachymesophalangy of the 2^nd and 5^th fingers, brachydactyly of fingers and toes with or without 2/3 and/or 4/5 toe syndactylies, ii) microcephaly, and iii) radiographs of the feet to look for amesophalangy of toes. Extension of the genetic screening is required to eliminate the possibility of two independent conditions. In addition to the previous recommendations, we advocate for a set of recommendations for evaluation of FS1 patients following initial diagnosis: systematic search of deafness, verification of the flexion of the interphalangeal joints of the thumbs, laryngoscopy in case of stridor or swallowing disorders, and finally systematic cerebral MRI.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105049"},"PeriodicalIF":1.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174369","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":"Late-onset Vitamin B6-dependent epilepsy caused by compound heterozygous pathogenic PLPBP variants.","authors":"Sadao Nakamura, Yasutsugu Chinen, Hirotaka Minema, Ryoko Honda, Tomonori Ono, Takeshi Mizuguchi, Naomichi Matsumoto, Koichi Nakanishi","doi":"10.1016/j.ejmg.2025.105047","DOIUrl":"https://doi.org/10.1016/j.ejmg.2025.105047","url":null,"abstract":"<p><p>Evidence has shown that pathogenic variants of the PLPBP gene can cause vitamin B6-dependent epilepsy, a condition characterized by neonatal-onset seizures that respond to vitamin B6 supplementation. In this paper, we report a case of vitamin B6-dependent epilepsy in a Japanese girl caused by compound heterozygous variants in PLPBP, NM_007198.4: c.275A>G (p. H92R) (novel) /c.319G>A (p. A107T) (reported), which developed when the patient was just 8 months old but was diagnosed at 10 years of age. Even after the neonatal period, vitamin B6-dependent epilepsy should be considered as a differential diagnosis of refractory epilepsy, with genetic analysis being useful for its diagnosis and treatment.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":" ","pages":"105047"},"PeriodicalIF":1.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112311","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":"ARID1A gene variants and fetal hydrocephalus: First evidence of mRNA decay escape","authors":"Yuya Tanaka ,&nbsp;Mamiko Yamada ,&nbsp;Fuyuki Miya ,&nbsp;Toshimitsu Otani ,&nbsp;Yoshifumi Kasuga ,&nbsp;Hisato Suzuki ,&nbsp;Noboru Inagaki ,&nbsp;Susan M. White ,&nbsp;Mamoru Tanaka ,&nbsp;Kenjiro Kosaki","doi":"10.1016/j.ejmg.2025.105048","DOIUrl":"10.1016/j.ejmg.2025.105048","url":null,"abstract":"<div><div>Germline variants in <em>ARID1A</em> have been associated with the so-called BAFopathies, including Coffin-Siris syndrome, which is characterized by hypertrichosis, short fifth finger, thin upper lip, and thick lower lip, is associated with a unique episignature. Hydrocephalus has not been considered part of BAFopathy until recently, when <em>ARID1A</em> variants were implicated in prenatal-onset hydrocephalus. It remains unknown whether <em>ARID1A</em>-associated hydrocephalus is linked to a specific class of variants and whether it exhibits an episignature comparable to that of BAFopathies. We conducted genomic and epigenomic analyses on a fetus diagnosed with severe hydrocephalus on prenatal ultrasound at 19 weeks. After detailed genetic counseling, the pregnancy was terminated at 21 weeks. The delivered fetus exhibited short fifth fingers, thin upper lip, and thick lower lip. Postmortem exome sequencing using umbilical cord blood identified a <em>de novo</em> heterozygous frameshift variant in the last exon of <em>ARID1A</em> (NM_006015.6:c.5259_5262dupGTCT, p.(Ser1755Valfs∗2)). The frameshift variant in the last exon was expected to escape nonsense-mediated mRNA decay (NMD), and we did confirm this through RNA-seq. Concurrent episignature analysis by nanopore sequencing and a support vector machine-based classifier showed that the fetus maps to the BAFopathy group rather than a separate position on the UMAP. Genotype-phenotype correlation analysis of unpublished data from previous reports regarding hydrocephalus and potential NMD escape, with input from the original authors, indicated that the association remains ambiguous. Hence, <em>ARID1A</em>-associated hydrocephalus occurs within the broader clinical and epigenomic spectrum of BAFopathies, but a distinct genetic mechanism caused by NMD escape is unlikely to play a role.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105048"},"PeriodicalIF":1.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079864","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":"Concurrent inheritance of achromatopsia and MMAT syndrome in a pedigree: Genetic and clinical insights","authors":"Maryam Aghasipour ,&nbsp;Sina Zoghi ,&nbsp;Afrooz Feili ,&nbsp;Hossein Jafari Khamirani ,&nbsp;Mehrdad Afarid ,&nbsp;Ehsan Namvar ,&nbsp;Seyed Alireza Dastgheib ,&nbsp;Seyed Mohammad Bagher Tabei ,&nbsp;Maryam Feili ,&nbsp;Mehdi Dianatpour","doi":"10.1016/j.ejmg.2025.105045","DOIUrl":"10.1016/j.ejmg.2025.105045","url":null,"abstract":"<div><h3>Background</h3><div>Achromatopsia is a rare type of retinal dystrophy presenting with decreased visual acuity, pendular nystagmus, photophobia, impaired color discrimination, and central scotoma. In this study, we investigated achromatopsia in a proband and his family.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing identified two novel variants in <em>PDE6H</em> and <em>ADAMTS18</em>. The presence of the variants was confirmed by Sanger sequencing and it was further utilized to determine the zygosity status of other family members. Lastly, the clinical presentations of the patients were thoroughly assessed.</div></div><div><h3>Results</h3><div>We identified two novel variants in two genes among six patients from a pedigree: <em>PDE6H</em> (NM_006205.3):c.35C &gt; G (p.SER12TER) and <em>ADAMTS18</em> (NM_199355.4):c.3139C &gt; T (p.ARG1047TER). The proband and two of his sisters were homozygous for the variant in PDE6H and heterozygous for the other one. The siblings complained of decreased visual acuity, impaired color discrimination, photophobia, and myopia. Ellipsoid zone disruption and pendular nystagmus were also noted in two and three of the patients, respectively. Two affected patients were heterozygous for the variant identified in <em>PDE6H</em> and homozygous for the variant detected in <em>ADAMTS18</em>. These two are the second generation of the family, born to non-consanguineous parents. Both presented with microcornea, myopia, and telecanthus. Punctual atresia and strabismus were also noted.</div></div><div><h3>Conclusion</h3><div>Pathogenic variants in <em>PDE6H</em> and <em>ADAMTS18</em> can cause a broad range of ophthalmic disorders. We suggest that the study of rare congenital genetic diseases in developing countries should be prioritized due to the differences in their environments and the issues care givers are confronted with when trying to face them.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105045"},"PeriodicalIF":1.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063779","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":"COL12A1 gene mutation is associated with habitual patellar dislocation: a case report and literature review","authors":"Qinying Feng ,&nbsp;Chao Feng ,&nbsp;Xiaoyu Song ,&nbsp;Xinzhong Zhou ,&nbsp;Zhihao Chen","doi":"10.1016/j.ejmg.2025.105046","DOIUrl":"10.1016/j.ejmg.2025.105046","url":null,"abstract":"<div><div>Variants within COL12A1 have been associated with the occurrence and progression of a number of musculoskeletal disorders. Here, we report a case of patellar dislocation and limited mobility in a 13-year-old patient and genetic determination of the etiology of their condition utilizing diagnostic whole-exome sequencing. The patient underwent diagnostic whole-exome sequencing to look for pathogenic variants, which were classified using the ACMG classification standards. A heterozygous nucleotide variant (NM_004370.6: c.8179-2A &gt; G) in intron 53 of the COL12A1 gene was identified and resulted in a splicing abnormality deemed pathogenic. In conclusion, the heterozygous nucleotide variant in intron 53 of COL12A1 has been associated with patellar dislocation and limited mobility of the knee.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105046"},"PeriodicalIF":1.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058457","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":"Innovative treatments of pediatric spinal muscular atrophy: The decision-making process in France","authors":"Maelle Biotteau ,&nbsp;Juliette Ropars ,&nbsp;Brigitte Chabrol ,&nbsp;Isabelle Desguerre ,&nbsp;Christine Barnéria ,&nbsp;Claude Cances","doi":"10.1016/j.ejmg.2025.105044","DOIUrl":"10.1016/j.ejmg.2025.105044","url":null,"abstract":"<div><div>Spinal muscular atrophy (SMA) is a devastating early-onset genetic disease characterized by motor neuron degeneration. For several years, an early access program has facilitated the use of three innovative therapies in France. To better define the therapeutic strategy following innovative therapy approval, an online expert committee within the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) evaluates early diagnosed children and treatment-naive SMA cases during pediatric SMA multidisciplinary team meetings (<em>ps</em>MTMs). The decision process leading to molecule choice or palliative care encompasses pretreatment data collection, case presentation during <em>ps</em>MTMs, decision support, collective decision-making, and consensus, including the place assigned to parents. The process of setting up a nationwide online network of experts seems to be an effective, reactive and useful procedure in choosing the appropriate therapeutic option for newly diagnosed SMA children.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105044"},"PeriodicalIF":1.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039508","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":"Diagnostic yield of whole exome sequencing in a cohort of 825 patients","authors":"Peter Førster Andersen ,&nbsp;Jakob Ek ,&nbsp;Helena Gásdal Karstensen ,&nbsp;Mads Bak ,&nbsp;Sabine Weller Grønborg ,&nbsp;Hanne Buciek Hove ,&nbsp;Birgitte Diness ,&nbsp;Tina Duelund Hjortshøj ,&nbsp;Trine Bjørg Hammer ,&nbsp;Christina Høi-Hansen ,&nbsp;Bitten Schönewolf-Greulich ,&nbsp;Anne-Marie Bisgaard ,&nbsp;Morten Duno ,&nbsp;Elsebet Østergaard","doi":"10.1016/j.ejmg.2025.105043","DOIUrl":"10.1016/j.ejmg.2025.105043","url":null,"abstract":"<div><div>Genetic testing plays a significant role in rare disease diagnostics. The most widespread technology for genetic testing of patients is <em>next generation sequencing</em> or <em>second-generation sequencing, including whole exome sequencing</em> (WES). Our laboratory performed diagnostic WES on 1660 samples representing 825 index patients aged 0–84 years between 2014 and 2020. The cohort is comprised of consecutive patients with a rare disease referred for diagnostic WES with analysis of all known disease genes. The main referrals were paediatric, clinical genetic and adult neurology departments.</div><div>Patients’ symptoms were translated to terms in the Human Phenotype Ontology (HPO) system and each symptom assigned to a single top-level HPO term. Variants were classified according to ACMG-AMP guidelines.</div><div>The diagnostic yield in this cohort was 33.7 % with 278 patients receiving a genetic diagnosis.</div><div>Patients with complex phenotypes with involvement of several organ systems were more likely to receive a genetic diagnosis. Higher diagnostic yields were seen for phenotypes including growth abnormalities, abnormalities of the ear or of the musculoskeletal system as well.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"78 ","pages":"Article 105043"},"PeriodicalIF":1.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999917","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}