More RP, Sumathipala D, Dolling H
… +5 more, Downes K, Bowdin S, Ahn J, Morris S, Rowitch DH
Eur J Med Genet
· 2025 Dec · PMID 41033412
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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) res...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.
Ferroul F, Snanoudj S, Leterme G
… +15 more, Mezouaghi K, Kieffer-Traversier M, Celse T, Dospeux J, Huby T, Marzin P, Morel G, Payet F, Remy M, Sennsfelder L, Spondenkiewicz M, Roy-Doray B, Amiel J, Pingault V, Alessandri JL
Eur J Med Genet
· 2025 Dec · PMID 41005613
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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...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 2nd and 5th 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.
Nakamura S, Chinen Y, Minema H
… +5 more, Honda R, Ono T, Mizuguchi T, Matsumoto N, Nakanishi K
Eur J Med Genet
· 2025 Dec · PMID 40976369
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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 re...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.
Tanaka Y, Yamada M, Miya F
… +7 more, Otani T, Kasuga Y, Suzuki H, Inagaki N, White SM, Tanaka M, Kosaki K
Eur J Med Genet
· 2025 Dec · PMID 40962111
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Germline variants in ARID1A 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 asso...Germline variants in ARID1A 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 ARID1A variants were implicated in prenatal-onset hydrocephalus. It remains unknown whether ARID1A-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 de novo heterozygous frameshift variant in the last exon of ARID1A (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, ARID1A-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.
Aghasipour M, Zoghi S, Feili A
… +7 more, Jafari Khamirani H, Afarid M, Namvar E, Dastgheib SA, Tabei SMB, Feili M, Dianatpour M
Eur J Med Genet
· 2025 Dec · PMID 40946907
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BACKGROUND: 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 a...BACKGROUND: 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. METHODS: Whole-exome sequencing identified two novel variants in PDE6H and ADAMTS18. 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. RESULTS: We identified two novel variants in two genes among six patients from a pedigree: PDE6H (NM_006205.3):c.35C > G (p.SER12TER) and ADAMTS18 (NM_199355.4):c.3139C > 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 PDE6H and homozygous for the variant detected in ADAMTS18. 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. CONCLUSION: Pathogenic variants in PDE6H and ADAMTS18 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.
Eur J Med Genet
· 2025 Dec · PMID 40945601
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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...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 > 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.
Biotteau M, Ropars J, Chabrol B
… +3 more, Desguerre I, Barnéria C, Cances C
Eur J Med Genet
· 2025 Dec · PMID 40935015
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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 F...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 (psMTMs). The decision process leading to molecule choice or palliative care encompasses pretreatment data collection, case presentation during psMTMs, 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.
Andersen PF, Ek J, Karstensen HG
… +11 more, Bak M, Grønborg SW, Hove HB, Diness B, Hjortshøj TD, Hammer TB, Høi-Hansen C, Schönewolf-Greulich B, Bisgaard AM, Duno M, Østergaard E
Eur J Med Genet
· 2025 Dec · PMID 40907741
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Genetic testing plays a significant role in rare disease diagnostics. The most widespread technology for genetic testing of patients is next generation sequencing or second-generation sequencing, including whole exome se...Genetic testing plays a significant role in rare disease diagnostics. The most widespread technology for genetic testing of patients is next generation sequencing or second-generation sequencing, including whole exome sequencing (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. 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. The diagnostic yield in this cohort was 33.7 % with 278 patients receiving a genetic diagnosis. 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.
Schumann I, Abou Jamra R, Jauss RT
… +6 more, Karnstedt M, Specht U, Zacher P, Woermann F, Yaron Y, Popp B
Eur J Med Genet
· 2025 Oct · PMID 40850669
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Defective neuronal migration causes lissencephaly (LIS), a neurodevelopmental disorder (NDD) with a smooth cerebral surface and abnormal cortical thickness. Variants in CEP85L are linked to posterior predominant LIS, but...Defective neuronal migration causes lissencephaly (LIS), a neurodevelopmental disorder (NDD) with a smooth cerebral surface and abnormal cortical thickness. Variants in CEP85L are linked to posterior predominant LIS, but the phenotype and genotype are unclear. Three new unrelated cases of CEP85L-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 CEP85L 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 de novo variants, 10 mother-father variants, and 13 variants with unknown inheritance. Genotype-phenotype correlations in CEP85L-associated LIS show that stronger splice and germline variants often cause more severe symptoms than mosaic variants. To reduce confusion caused by alternative CEP85L transcripts, we recommend NM_001042475 for variant interpretation. These findings improve this disorder's genetic diagnostics and counseling framework.
Eur J Med Genet
· 2025 Oct · PMID 40850668
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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...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.
Eur J Med Genet
· 2025 Oct · PMID 40840652
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Chitayat syndrome (CHYTS) is an autosomal dominant disorder caused by variants in the ETS2 repressor factor (ERF) gene, located on 19q13.2. This gene encodes the ERF protein. The syndrome is extremely rare, with only 13...Chitayat syndrome (CHYTS) is an autosomal dominant disorder caused by variants in the ETS2 repressor factor (ERF) gene, located on 19q13.2. This gene encodes the ERF protein. The syndrome is extremely rare, with only 13 patients reported to date. We present a patient of CHYTS resulting from a c.1201_1202del (p.Lys401Glufs∗10) frameshift variant in the ERF (NM_001429.3) gene. The patient, a 10-year-old girl, exhibited typical features of the syndrome such as short stature, facial dysmorphism, and early developmental delay. She was treated with recombinant human growth hormone for ∼5 years due to her short stature. During treatment, no complications such as increased intracranial pressure, hypothyroidism, or pancreatic dysfunction were noted. However, the growth response was suboptimal, with a total height increase of 25.4 cm. This patient provides valuable insights into the clinical manifestations and treatment outcomes associated with ERF(NM_001429.3) gene variants, contributing to the existing knowledge and potentially aiding clinicians in understanding similar patients.
Braun D, Amylidi-Mohr S, Ahrens O
… +3 more, Trippel M, Schiller R, Zweier C
Eur J Med Genet
· 2025 Oct · PMID 40835206
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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-...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 LIFR or the interleukin-6 cytokine family signal transducer encoding IL6ST are causative. So far, five individuals from three unrelated families were described with IL6ST 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 IL6ST in the fetus. The further course of the pregnancy was complicated by early rupture of the membranes and preeclampsia. The fetus died in utero 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. With this case report, we further delineate the molecular and clinical spectrum of IL6ST related Stüve-Wiedemann syndrome.
Tanaka Y, Ikenoue S, Ueno A
… +8 more, Masugi Y, Yamada M, Suzuki H, Otani T, Fukutake M, Kasuga Y, Kosaki K, Tanaka M
Eur J Med Genet
· 2025 Oct · PMID 40829732
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Mirror syndrome is a rare obstetric condition characterized by maternal fluid retention mirroring fetal hydrops. Placental ectopic liver tissue is an extremely rare non-trophoblastic placental tumor, potentially arising...Mirror syndrome is a rare obstetric condition characterized by maternal fluid retention mirroring fetal hydrops. Placental ectopic liver tissue is an extremely rare non-trophoblastic placental tumor, potentially arising from aberrant hepatoblast migration. While its association with fetal hydrops has been reported, the clinical significance remains uncertain. We present a patient of maternal mirror syndrome linked to fetal hydrops due to a de novo SOS1 variant, with histopathological identification of placental ectopic liver tissue. A 32-year-old woman was admitted at 31 weeks' gestation with fetal hydrops, presenting with bilateral pleural effusions, ascites, and subcutaneous edema. Due to worsening maternal pleural effusion, she was transferred to our hospital at 31 weeks and 6 days. Given progressive maternal and fetal deterioration, an emergency cesarean section was performed at 32 weeks due to concerns regarding maternal mirror syndrome. The female infant was delivered with severe respiratory distress and succumbed at 9 days of age. Trio-based exome sequencing identified a de novo heterozygous SOS1 variant (NM_005633.4:c.512T > A [p.V171G]), confirming a postmortem diagnosis of Noonan syndrome. Histopathological analysis of the placenta revealed ectopic liver tissue within the villi, confirmed by positive immunostaining for hepatocyte markers. A recent report of RIT1-associated mirror syndrome and non-immune hydrops fetalis (NIHF) further supports the role of Rasopathies in the pathogenesis of mirror syndrome. Our findings confirm that mirror syndrome is a potential manifestation of Rasopathies, while the role of ectopic liver tissue in the placenta remains uncertain. Future research should focus on genetic factors underlying mirror syndrome rather than incidental placental anomalies.
van Till SAL, Bouman A, Kleefstra T
… +1 more, Bunnik EM
Eur J Med Genet
· 2025 Oct · PMID 40829731
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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 suppor...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.
Dehghanzad R, Eshaghkhani Y, Saberi M
… +3 more, Jamshidifar M, Karimzadeh P, Keramatipour M
Eur J Med Genet
· 2025 Oct · PMID 40812465
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The HECW2 gene encodes a HECT (homologous to E6-AP carboxy terminus)-type E3 ubiquitin ligase that plays a critical role in neurodevelopment. Pathogenic variants in HECW2 are associated with a neurodevelopmental disorder...The HECW2 gene encodes a HECT (homologous to E6-AP carboxy terminus)-type E3 ubiquitin ligase that plays a critical role in neurodevelopment. Pathogenic variants in HECW2 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 HECW2 gene may cause the disease with autosomal recessive inheritance. 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 HECW2 (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. This study expands the phenotype and genetic spectrum of HECW2-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 HECW2 variants are essential to deepen our understanding of its role in neurodevelopment and refine diagnostic and therapeutic approaches.
Skei Sekkelsten AI, Skattør TH, Holmstrøm H
… +2 more, Krohg-Sørensen K, Paus B
Eur J Med Genet
· 2025 Oct · PMID 40812464
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Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder caused by heterozygous variants in COL3A1, leading to tissue and vessel fragility alongside an increased risk of potentially fatal aneurys...Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder caused by heterozygous variants in COL3A1, 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. 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. 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. 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.
Eur J Med Genet
· 2025 Oct · PMID 40783012
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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, w...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.
Ducatel P, Verger A, Selton M
… +5 more, Renaud M, Puisieux S, Grosset A, Hopes L, Michaud M
Eur J Med Genet
· 2025 Oct · PMID 40721190
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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...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. 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.
Neuens S, Soblet J, Penninckx A
… +34 more, Detry C, Badoer C, Desmyter L, Peyrassol X, Wilkin F, Busson A, Bruneau M, Grenet ML, Le Morillon A, Aeby A, Deconinck N, Prigogine C, Monier A, Juvené E, Balfroid T, Van Hecke A, Christiaens F, Depondt C, Brachet C, Delvenne V, Lufin N, Bouysran Y, Kammoun M, Daneels D, Caljon B, Croes D, Olsen C, Van Dooren S, Migeotte I, Vandernoot I, Marangoni M, Coppens S, Smits G, Vilain C
Eur J Med Genet
· 2025 Aug · PMID 40592404
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Next generation sequencing has revolutionized the diagnostic approach for patients with neurodevelopmental disorders (NDDs), yields are however highly variable depending on the patient's phenotype. It is often challengin...Next generation sequencing has revolutionized the diagnostic approach for patients with neurodevelopmental disorders (NDDs), yields are however highly variable depending on the patient's phenotype. It is often challenging to predict which indications are likely to lead to a molecular diagnosis and which will benefit less from genetic testing. To identify phenotypic characteristics associated with higher diagnostic yields we conducted detailed phenotyping of a cohort of 868 children with NDD, who underwent clinical exome sequencing between 2016 and 2021. A molecular diagnosis was reached in 27 % of cases. Significantly higher yields of respectively 34 % and 32 % were observed in patients with intellectual disability (ID) or global developmental delay (GDD). Autism spectrum disorders (ASD) were less likely to result in a molecular diagnosis with a diagnostic yield of 16 %. Additional factors linked to higher yields included female gender, the presence of minor dysmorphic features - particularly involving the face, extremities, ears, eyes, and hair - and a syndromic phenotype. Additional CNV calling in a subset of 438 patients which consented to reanalysis of sequencing data added 1.5 % to diagnostic yield.
Magliulo S, Genovesi ML, Lucchetti L
… +4 more, Orlando V, Novelli A, Massella L, Terracciano A
Eur J Med Genet
· 2025 Aug · PMID 40543848
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Steroid-resistant nephrotic syndrome is a rare condition defined by early severe proteinuria associated with hypoalbuminemia, hyperlipidemia and possible edema, is usually caused by pathogenic variants in genes affecting...Steroid-resistant nephrotic syndrome is a rare condition defined by early severe proteinuria associated with hypoalbuminemia, hyperlipidemia and possible edema, is usually caused by pathogenic variants in genes affecting the establishment and maintenance of the glomerular filtration barrier; among these NPHS1 (19q13.12) and NPHS2 (1q25.2) are by far the two main autosomal recessive genes implicated. We report on a 23-year-old girl referred to our hospital for Steroid-resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis, onset at the age of 5 months. Next Generation Sequencing analysis showed the homozygous pathogenic variant c.413G > A in the NPHS2 gene, leading to the amino acid change p.Arg138Gln (rs74315342). By segregation study the father resulted heterozygous carrier of the same variants, while the mother emerged as wild-type. In order to investigate a possible chromosomal rearrangement in the maternal allele, SNP-array analysis was performed, revealing a paternally chromosome 1 isodisomy in the proband. Uniparental disomy of chromosome 1 is not associated with a specific phenotype but unmasks the autosomal recessive NPHS2 mutation paternally inherited and bring it to a homozygosity state. In conclusion, this clinical report demonstrates the importance of parental segregation analysis, especially in patients with recessive conditions, both to search for the disease specific genetic cause and to appropriately estimate the risk of recurrence in the family.