Eur J Med Genet
· 2026 Mar · PMID 41747888
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Myoclonus-dystonia syndrome (MDS) is an autosomal dominant movement disorder most caused by pathogenic variants in SGCE, an imprinted gene subject to maternal silencing. While numerous pathogenic variants have been repor...Myoclonus-dystonia syndrome (MDS) is an autosomal dominant movement disorder most caused by pathogenic variants in SGCE, an imprinted gene subject to maternal silencing. While numerous pathogenic variants have been reported, the extent and determinants of intrafamilial variability remain incompletely understood. We investigated a large French family in which ten individuals across three generations presented with myoclonic jerks, dystonia, or combined phenotypes. Trio whole-exome sequencing performed in the proband, her affected brother, and her affected father identified a heterozygous SGCE variant, NM_003919.3:c.406T > G, predicting a p.Cys136Gly substitution in a highly conserved cysteine-rich extracellular domain of ε-sarcoglycan. The variant segregated with disease in all clinically affected individuals for whom DNA was available and was absent from population databases. The phenotypic spectrum ranged from mild, stress-induced myoclonus in females to early-onset myoclonus with cervical dystonia and alcohol responsiveness in males, consistent with imprinting effects and sex-dependent modifiers. Variant interpretation using ACMG/AMP criteria (PM1, PM2, PM5, PP1-strong, PP2, PP3) supports a pathogenic classification. This previously unreported SGCE missense variant expands the mutational spectrum of MDS and further illustrates the substantial intrafamilial variability of SGCE-related disease.
Insalaco A, Rossi C, Bertucci E
… +6 more, Fiorentini C, Soresina A, Giliani S, Porta F, Berardi A, Lugli L
Eur J Med Genet
· 2026 Mar · PMID 41616907
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Cartilage hair hypoplasia (CHH) syndrome (OMIM #250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hypotrichosis and variable extra-skeletal manifestations, incl...Cartilage hair hypoplasia (CHH) syndrome (OMIM #250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hypotrichosis and variable extra-skeletal manifestations, including immunodeficiency, anemia, intestinal diseases, and predisposition to malignancies. CHH results from homozygous or compound heterozygous mutations in the RMRP gene on chromosome 9p13, which encodes an untranslated RNA component of mitochondrial RNA-processing endoribonuclease. RMRP pathogenic variants can also lead to Omenn Syndrome (OS) (OMIM #603554), a systemic inflammatory condition displaying neonatal erythroderma and immunodeficiency. This report highlights the genotypic and phenotypic overlap between CHH and OS, by presenting a newborn with skeletal dysplasia, immunodeficiency and neonatal onset erythroderma, carrying the homozygous NR_003051:n.35C > A variant in the RMRP gene.
Morana E, Baronio F, Lanari M
… +8 more, Candela E, Ortolano R, Bonetti S, Bronzetti G, Biasucci G, Hasan T, Ragni L, Donti A
Eur J Med Genet
· 2026 Mar · PMID 41611076
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BACKGROUND: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia...BACKGROUND: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Europe. Clinical onset typically occurs between 3 and 24 months of life with hypoketotic hypoglycemia, while neonatal presentations are less common. Although the disorder classically manifests with metabolic decompensation, atypical cardiac involvement has occasionally been reported but remains exceedingly rare. MCADD is included in many newborn screening programs, enabling early detection and timely management. CASE PRESENTATION: We report a full-term female neonate who, at 3 days of life, developed severe metabolic decompensation with refractory supraventricular tachyarrhythmias, severe systolic dysfunction, and biventricular dilation requiring maximal inotropic support. Expanded newborn screening revealed a profile consistent with MCADD, and genetic testing identified a homozygous variant in the ACADM gene, described according to HGVS nomenclature as ACADM(NM_000016.6):c.985A > C p.(Lys329Gln). Disease-specific management, including high-rate intravenous glucose administration, carnitine supplementation, and a tailored low-fat diet, resulted in complete normalization of cardiac function within 48 hours. DISCUSSION: This case represents a tachycardiomyopathy-like presentation of neonatal-onset MCADD, a novel and rarely described cardiac phenotype. It emphasizes the importance of considering fatty acid oxidation disorders in the differential diagnosis of unexplained arrhythmias and cardiomyopathy in neonates, particularly before newborn screening results are available. CONCLUSIONS: Early diagnosis and prompt initiation of metabolic treatment are essential to reverse potentially life-threatening cardiac manifestations in MCADD. This report highlights a novel phenotype and expands the clinical spectrum of neonatal-onset MCADD.
Tsurubuchi T, Yamaki Y, Fukushima H
… +11 more, Sato K, Takahashi H, Karita H, Sakamoto N, Mizumoto M, Nakai K, Sakurai H, Muroi A, Matsuda M, Takada H, Ishikawa E
Eur J Med Genet
· 2026 Mar · PMID 41547400
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Paediatric cancer predisposing factors (CPFs), such as DICER1 syndrome, Li-Fraumeni syndrome, and SMARC-related syndromes, are increasingly being identified through genome-wide sequencing of surgical specimens. Among the...Paediatric cancer predisposing factors (CPFs), such as DICER1 syndrome, Li-Fraumeni syndrome, and SMARC-related syndromes, are increasingly being identified through genome-wide sequencing of surgical specimens. Among these, mutations in the SWItch/Sucrose Non-Fermentable chromatin-remodelling complex, particularly involving the SMARCE1 gene, have been implicated in various paediatric tumours, including clear cell meningioma (CCM). However, the role of SMARCE1 mutations in other rare tumours like chordoma remains undetermined. TBXT is a gain-of-function driver mutation of chordoma alongside upregulated transforming growth factor beta 1 (TGFβ1) and epidermal growth factor receptor (EGFR). Herein, we report a rare case of thoracic chordoma with sudden abdominal pain after treatment for intracranial CCM. Germline analyses of surgical specimens from CCM and chordoma showed heterozygous mutations in both the SMARCE1 (chromosome 17q21.2) and TBXT (brachyury, chromosome 6q27) genes. Somatic mutation analyses showed loss of heterozygosity at the SMARCE1 gene region in both CCM and chordoma surgical specimens, as well as at the TBXT gene region in CCM, but not in chordoma. We speculated that both TBXT and SMARCE1 might indirectly promote EGFR signalling to drive chordoma cell proliferation and survival, although the direct interaction between TBXT and SMARCE1 is unknown. To our knowledge, this is the first report of a patient with a spinal chordoma after CCM treatment, suggesting that SMARCE1 is a candidate pathological factor in chordoma.
Buoncuore G, Salvatore M, Rocchetti A
… +13 more, Facciaroni L, Veneselli E, Elia M, Russo S, Armando M, Germano M, Prisco T, Sartori S, Marinella G, Battini R, Gobbi G, Torreri P, Angelman Syndrome Registry working group
Eur J Med Genet
· 2026 Jan · PMID 41525882
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BACKGROUND: Angelman syndrome (AS) is a rare and heterogeneous genetic disorder characterized by intellectual and psychomotor delay, speech deficits, seizures and behavioural issues. To evaluate the feasibility of collec...BACKGROUND: Angelman syndrome (AS) is a rare and heterogeneous genetic disorder characterized by intellectual and psychomotor delay, speech deficits, seizures and behavioural issues. To evaluate the feasibility of collecting data by many Italian centers involved in pathology management, and to investigate the relationship between various symptoms and genotypes, a dedicated AS registry was developed. This study aims to present preliminary findings from the Italian AS registry (IReAS), with a specific focus on exploring genotype-phenotype correlations. MATERIALS AND METHODS: The IReAS, established in 2020, aims to collect information from 14 different Italian referral. It includes demography, diagnosis and genetic, patient status, therapeutic interventions and mortality data collection. RESULTS: 213 patients (55.4 % female vs 44.6 % male) were included in the IReAS during the 2020-24 period. Average age at genetic diagnosis was 3.8 years; 63 % of patients was paediatric; 70.4 % of subjects had maternal deletion. Most patients exhibited global developmental delay (100 %), movement disorders (94.8 %), behavioral abnormalities (96.2 %), and a total lack of language development (95.8 %). Epilepsy is also highly prevalent (80.3 %), with a significantly higher incidence in patients with maternal deletion compared to non-deletion groups (88 % vs 61.9 %). CONCLUSIONS: The IReAS provides comprehensive data on the diagnosis, genetic subtypes and clinical features of AS patients. It can facilitate genotype-phenotype correlation analyses, offering insights into the AS natural history and potential implications for research on targeted therapies.
Romano F, Shams Nosrati MS, Madia F
… +8 more, Ognibene M, Traverso M, Breda M, Dostmohammadi A, Scala M, Zara F, Mancardi MM, Capra V
Eur J Med Genet
· 2026 Jan · PMID 41344425
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The Cut Like Homeobox 2 (CUX2) gene encodes a transcription factor critical for neuronal development. Monoallelic pathogenic CUX2 variants are associated with developmental and epileptic encephalopathy 67 (DEE67), an aut...The Cut Like Homeobox 2 (CUX2) gene encodes a transcription factor critical for neuronal development. Monoallelic pathogenic CUX2 variants are associated with developmental and epileptic encephalopathy 67 (DEE67), an autosomal dominant disorder characterized by variable clinical pictures including early-onset seizures, global developmental delay, and intellectual disability. While most variants described in the literature are missense, only one frameshift variant is reported as likely pathogenic for DEE67 in the ClinVar database. In this study, we report the patient, an 8-year-old girl with clinical features compatible with DEE67, who carries a novel de novo frameshift variant, c.633_636del p.(His211Glnfs∗3), in the CUX2 gene. Although formally classified as a Variant of Uncertain Significance (VUS) based on stringent ACMG criteria, the variant is predicted to be a null allele, likely leading to CUX2 haploinsufficiency via Nonsense-Mediated Decay (NMD). Clinically, her epileptic phenotype consisted of a single generalized tonic-clonic seizure, of milder entity and more treatment-responsive than those of other reported DEE67 cases. This report expands the genotypic spectrum of CUX2-related disorders and provides further evidence supporting haploinsufficiency as a pathogenic mechanism, while describing a milder clinical presentation that broadens the phenotypic spectrum of DEE67.
Fetecau AC, Grotto S, Anselem O
… +4 more, Molac C, Bertrand J, Lœuillet L, Attie-Bitach T
Eur J Med Genet
· 2026 Jan · PMID 41330542
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Occipital encephaloceles are neural tube abnormalities characterized by a median defect of the occipital bone with herniation of brain structures usually contained in a membranous sac. Intracranial structures that protru...Occipital encephaloceles are neural tube abnormalities characterized by a median defect of the occipital bone with herniation of brain structures usually contained in a membranous sac. Intracranial structures that protrude range from meninges (meningocele) to cerebral tissue such as occipital lobes, rarely cerebellum, brainstem or torcula. We present two fetal sibs with occipital meningocele caused by a maternal MSX2 variant identified by whole genome sequencing. Apart from the occipital meningocele, other cerebral abnormalities were found which led to the termination of the two pregnancies. The autopsy confirmed the prenatal findings. Upon clinical examination of the mother, a small scalp defect was discovered consistent with MSX2 gene variant. To our knowledge, only one case of occipital meningocele caused by MSX2 gene haploinsufficiency has been reported, with maternal inheritance. This paper is aimed at confirming the link between MSX2 gene variant and fetal occipital encephalocele, as well as its clinical variability.
Gupta S, Bawa P, Kumari A
… +3 more, Panigrahi I, Srivastava P, Kaur A
Eur J Med Genet
· 2025 Dec · PMID 41318057
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BACKGROUND: Face2Gene and GestaltMatcher are two artificial intelligence-based tools for facial image analysis and syndrome suggestion. MATERIAL AND METHODS: Frontal photographs of patients (one photograph per patient) w...BACKGROUND: Face2Gene and GestaltMatcher are two artificial intelligence-based tools for facial image analysis and syndrome suggestion. MATERIAL AND METHODS: Frontal photographs of patients (one photograph per patient) with molecularly confirmed diagnosis were uploaded on Face2Gene and GestaltMatcher. The position at which the correct syndrome was listed, and the gestalt scores were noted. The top-3,10 and 30 accuracy was calculated. RESULTS: A total of 159 patient photographs of 72 different syndromes were analysed. The top-3 accuracy of Face2Gene vs GestaltMatcher was 77 % and 58 % and top-10 accuracy 85 % and 71 % respectively. GestaltMatcher could correctly identify in the top-10 category, 2 out of 7 (28.5 %) monogenic syndromes for which Face2Gene did not have a composite model. Both the tools performed significantly better for rare syndromes as compared to ultrarare syndromes. We also demonstrate through two of our cases the tools' potential to support variant interpretation in clinical practice. CONCLUSION: The combined use of Face2Gene and GestaltMatcher has a considerable potential to support the diagnostic decision process in routine clinical settings.
Giraud S, Berthet P, Abadie C
… +20 more, Andrieu N, Benusiglio PR, Bonadona V, Caron O, Corsini C, Coupier I, Crivelli L, Delnatte C, Devulder P, DE Pauw A, Dussart S, Gimenez-Roqueplo AP, Lejeune-Dumoulin S, Moretta J, Muller M, Tinat J, Richard S, Nogues C, Burnichon N, pour le réseau PREDIR et le Groupe génétique et cancer d'Unicancer
Eur J Med Genet
· 2025 Dec · PMID 41270862
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INTRODUCTION: Renal cancers are inherited in about 5 % of cases and are associated with several genetic syndromes. Genetic testing is recommended for selected patients suspected of having hereditary syndromes. In the abs...INTRODUCTION: Renal cancers are inherited in about 5 % of cases and are associated with several genetic syndromes. Genetic testing is recommended for selected patients suspected of having hereditary syndromes. In the absence of guidelines regarding which genes should be included for carrying out genetic screening of these individuals, discrepancies existed among the next generation sequencing (NGS) multi-gene panels (MGP) used in French laboratories. There was therefore a clear need to standardise practices and offer patients with renal cancer a consensus-based genetic testing in France. METHODS: A working group comprising national experts from the French Genetic and Cancer Group Unicancer (GGC) and from the French network on Hereditary PREDIspositions to Renal Cancer (PREDIR) and encompassing medical geneticists, genetic counsellor, molecular biologists and epidemiologists was established. The objective was to define a list of clinically relevant genes that should be included in a "GGC-PREDIR" approved NGS MGP for patients with renal cancer. A list of 32 genes of interest was compiled following an exhaustive and critical review of the literature. The inclusion or exclusion of each gene was determined based on available data regarding risk, prevalence and analyses published from large studies of patients. RESULTS: The French group of experts defined a list of 12 genes of clinical and genetic counselling relevance comprising BAP1, FH, FLCN, MET, PTEN, SDHA, SDHB, SDHC, SDHD, TSC1, TSC2 and VHL to be included in the national recommended "renal cancer" NGS MGP. For each of these genes, recommendations for renal surveillance are proposed. CONCLUSION: Unlike hereditary predisposition to breast or colon cancer, hereditary renal cancer predispositions are rare syndromes and risk estimates are lacking for most of them. Prospective studies are needed to improve our knowledge. The GGC-PREDIR experts retained 12 genes for inclusion in the NGS MGP for renal cancer patients. However, the panel will be expanded on the basis of regularly updated data from the medical literature.
Cocchella G, Phung L, Wood E
… +17 more, Egleston B, Hoffman-Andrews L, Brown S, Ofidis D, Mim R, Griffin H, Fetzer D, Owens A, Domchek S, Pyeritz R, Katona BW, Kallish S, Sirugo G, Weaver J, Nathanson KL, Rader DJ, Bradbury AR
Eur J Med Genet
· 2025 Dec · PMID 41241316
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While research participants report interest in receiving genetic research results, how best to return results to ensure medical benefits remains unclear. In the Penn Medicine Biobank Return of Results Study, participants...While research participants report interest in receiving genetic research results, how best to return results to ensure medical benefits remains unclear. In the Penn Medicine Biobank Return of Results Study, participants receive results through a digital intervention or a genetic counselor and are recommended to complete clinical confirmation testing and a visit in clinical genetics. We reviewed EHR encounters to understand longitudinal clinical outcomes in 16 patients who completed all steps (Group A), 8 patients who did not complete the clinical genetics visit (Group B), and 21 patients who did not complete confirmation testing or the clinical genetics visit (Group C). Most participants in Group A (69 %) had evidence of adherence to medical recommendations. Some patients faced usual barriers to care and related to comorbid conditions. In contrast, most participants in Group B (75 %) did not have evidence of discussing their confirmed result with a provider or adherence to medical recommendations. Most participants in Group C (71 %) did not have evidence of discussing their research results with providers, although one discussed their unconfirmed result. Men were less likely to complete all steps (Group A), and participants with cardiovascular results were less likely to complete the medical visit (Group B). There was no documentation regarding testing in relatives in any non-genetics encounters for any groups. These data suggest that the steps following return of research results may be critical to realizing the medical benefits of returning actionable genetic research results and highlight the importance of collecting systematic longitudinal outcomes. CLINICAL TRIAL REGISTRATION: NCT04242667.
Howat J, Vigneswaran T, Papageorghiou A
… +1 more, Mansour S
Eur J Med Genet
· 2025 Dec · PMID 41224194
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Pathogenic variants in GATA4, a transcription factor, are predominantly associated with congenital heart defects and gonadal abnormalities. We describe a case of a maternally inherited GATA4 pathogenic variant (c.474C > ...Pathogenic variants in GATA4, a transcription factor, are predominantly associated with congenital heart defects and gonadal abnormalities. We describe a case of a maternally inherited GATA4 pathogenic variant (c.474C > G p.[Tyr158Ter]) in a 21-week gestation fetus presenting with partial atrioventricular septal defect and congenital diaphragmatic hernia. Whilst there is a weight of evidence implicating GATA4 dysfunction in congenital diaphragmatic hernia, this is only the second report to our knowledge to identify a causative GATA4 variant with congenital diaphragmatic hernia.
He P, Zou S, Chen J
… +6 more, Wang M, Lin P, Lou J, Ma Z, Li Z, Yan T
Eur J Med Genet
· 2025 Dec · PMID 41213470
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Pathogenic variants in the NONO gene (MIM #300084) are responsible for X-linked syndromic intellectual developmental disorder-34 (MRXS34, MIM #300967) characterized by macrocephaly, dysmorphic facial features, global dev...Pathogenic variants in the NONO gene (MIM #300084) are responsible for X-linked syndromic intellectual developmental disorder-34 (MRXS34, MIM #300967) characterized by macrocephaly, dysmorphic facial features, global developmental delay, hypotonia, heart anomalies, and mild structural brain abnormalities. This report describes a 3-month-old male and a 7-month-old female presenting with microcephaly, dysmorphic facial features, developmental delay, hypotonia, congenital heart defects, abnormal kidney ultrasound, and abnormal cranial MRI findings. The male exhibited left ventricular noncompaction (LVNC), while the female also had abdominal distension and chronic constipation. Whole-exome sequencing (WES) was employed to identify the causative variants. A systematic review of MRXS34 clinical phenotypes was also conducted. WES revealed a novel maternally inherited Xq13.1 hemizygous deletion, encompassing exons 6-13 of the NONO gene in the male, and a recurrent de novo heterozygous c.344G > A (p.Arg115His) variant in NONO in the female. The latter demonstrated extreme X-chromosome inactivation (XCI) skewing. To date, 33 unrelated male cases of MRXS34 have been documented, and 27 NONO variants, have been identified worldwide. The phenotypes in our patients overlap with those previously reported or closely resemble those of MRXS34. Macrocephaly, corpus callosum anomalies, and LVNC exhibit relatively high penetrance but tend to worsen with age. Additionally, dysplastic pulmonary valve/pulmonary hypertension and recurrent chronic constipation episodes may be integral to an alternative NONO-related disorder. This study expands the phenotypic and allelic diversity of NONO-related disorder by providing further genotype-phenotype correlations from two additional cases. The co-occurrence of a NONO variant with extreme XCI skewing likely underpins the pathogenicity of this rare female case, which presents with severe phenotypes akin to those seen in male patients with MRXS34.
Kajiwara K, Liang Q, Uchiyama Y
… +16 more, Chong PF, Ichimiya Y, Monji N, Shimokawa S, Sonoda M, Watanabe E, Sakata A, Sonoda Y, Akamine S, Ishimura M, Murakami Y, Kunisaki Y, Sonoda KH, Matsumoto N, Sakai Y, Ohga S
Eur J Med Genet
· 2025 Dec · PMID 41203069
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BACKGROUND: Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (...BACKGROUND: Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. CLINICAL REPORT: A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. RESULTS: Exome sequencing identified a heterozygous CLN3 variant, NM_001042432.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178_180delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM_001042432.2:c.[295-2A > C]; [178_180delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. CONCLUSION: This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients.
Lauerova B, Mazanec R, Eggerman K
… +5 more, Safka Brozkova D, Lischka A, Seeman P, Mikula M, Lassuthova P
Eur J Med Genet
· 2025 Dec · PMID 41177402
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Biallelic variants in the FIG4 gene cause Charcot-Marie-Tooth type 4J (CMT4J) and Yunis-Varon syndrome. There is increasing evidence of phenotypic overlap between CMT4J and Yunis-Varon syndrome, which presents with perip...Biallelic variants in the FIG4 gene cause Charcot-Marie-Tooth type 4J (CMT4J) and Yunis-Varon syndrome. There is increasing evidence of phenotypic overlap between CMT4J and Yunis-Varon syndrome, which presents with peripheral neuropathy and central nervous system (CNS) abnormalities, particularly parkinsonism. We aim to extend and specify the phenotype-genotype correlation of the FIG4 variants by presenting four cases of CMT4J, including two with parkinsonism. All patients carried the pathogenic FIG4 variant c.122T > C p.(Ile41Thr) in compound heterozygosity with another variant: c.793C > T p.(Arg265∗), c.498-1G > A, or c.447-2A > C. Disease onset occurred in the first or second decade of life. All presented with demyelinating sensorimotor polyneuropathy, distal muscle weakness of the upper and lower limbs, and foot deformity. In one patient, the muscle weakness was asymmetrical. Two patients developed parkinsonism. Our findings expand the phenotypic spectrum of FIG4-related disorders, reinforcing the link between CMT4J and parkinsonism. These insights are crucial for improving genetic diagnosis and advancing potential therapeutic strategies.
Eur J Med Genet
· 2025 Dec · PMID 41161533
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There are conflicting reports on chromosome heteromorphisms. A large number of papers claim that these variants are found more frequently among infertile couples, especially with recurrent pregnancy loss and are even ass...There are conflicting reports on chromosome heteromorphisms. A large number of papers claim that these variants are found more frequently among infertile couples, especially with recurrent pregnancy loss and are even associated with congenital abnormalities. Other studies have found no evidence to support such claims. A critical review of these papers shows that at present there is no convincing evidence to show that heteromorphic chromosome variants, as described in the International System for Human Cytogenomic Nomenclature (ISCN, 2024), are harmful.
Zhang J, Deng Y, Huang Y
… +7 more, Hu D, Wu H, Lv T, Yang W, Wan L, Liu F, Hu J
Eur J Med Genet
· 2025 Dec · PMID 41130538
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BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease characterized by significant genetic heterogeneity. While the T-box transcription factor 1 (TBX1) gene is known to cause congenital...BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease characterized by significant genetic heterogeneity. While the T-box transcription factor 1 (TBX1) gene is known to cause congenital cardiovascular defects, it has not been previously associated with HCM. METHODS: Whole-exome sequencing (WES) was performed to identify causative gene mutations in a recently diagnosed Chinese family with HCM. The mutation was confirmed using Sanger sequencing, which was also employed to investigate familial co-segregation. A literature review was conducted to analyze previously reported TBX1 mutations and their associated phenotypes. RESULTS: A novel heterozygous frameshift mutation, TBX1 (NM_080647.1):c.3_27dup (p.Met10Alafs∗167), was identified in affected family members. Familial co-segregation analysis revealed that this mutation correlated with the HCM phenotype. To date, no previous studies have reported an association between TBX1 mutations and HCM, suggesting that this may represent a novel TBX1-related phenotype. CONCLUSION: This study identifies familial HCM as a new phenotype linked to TBX1 gene mutations. These findings expand the mutation and phenotype spectrum of TBX1 and emphasize the need for further research to understand the mechanisms by which the c.3_27dup (p.Met10Alafs∗167) mutation leads to HCM.
van der Tol L, de Jong M, Alders M
… +4 more, Wilke M, van der Schoot V, van Slegtenhorst MA, Goverde A
Eur J Med Genet
· 2025 Dec · PMID 41077274
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With new and increasingly sensitive techniques for genetic testing, genes that are newly related to a phenotype or disease are still identified, warranting for adequate phenotyping. Recently, 11 variants in the ZFX gene...With new and increasingly sensitive techniques for genetic testing, genes that are newly related to a phenotype or disease are still identified, warranting for adequate phenotyping. Recently, 11 variants in the ZFX gene were reported to cause a distinct X-linked neurodevelopmental disorder in 18 male patients, and a female was reported with hyperparathyroidism in concurrence with a ZFX variant. In this report, we present a male patient and his mother with a new likely pathogenic variant in the ZFX gene (NM_003410.4(ZFX): c.2363C > G, p. Pro788Arg). The phenotype of the patient includes a global neurodevelopmental delay and several additional features greatly overlapping with the phenotype in previously described patients, including facial features, hypotonia, diminished white matter and thin corpus callosum, inguinal and umbilical herniation, and ophthalmological abnormalities. An elevated PTH was noted, with normocalcemia, a possible early sign of hyperparathyroidism. Additionally, a small colon, signs of a bleeding diathesis and a cervical swelling of non-specific origin were present, which were not reported in patients with ZFX variants before. The mother presents with fatigue, low iron status and a slight elevation of PTH with normocalcemia. This report adds valuable data to the phenotypical spectrum of the ZFX-related neurodevelopmental disorder.
Peay H, Fischer R, McNiff M
… +17 more, Heslop E, Pierce A, Denger B, Camino E, Johnson A, Cope H, Hill C, Beaverson KL, Ganot A, Phillips D, Woollacott IOC, Bateman-House A, Flanigan KM, Goemans N, Servais L, Guglieri M, Mansfield C
Eur J Med Genet
· 2025 Dec · PMID 41075975
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Patient and caregiver treatment preferences should be incorporated into the drug development process. We updated a 2018 survey to reflect current knowledge about gene therapy for Duchenne muscular dystrophy (DMD) and obt...Patient and caregiver treatment preferences should be incorporated into the drug development process. We updated a 2018 survey to reflect current knowledge about gene therapy for Duchenne muscular dystrophy (DMD) and obtained new data in the U.S., U.K., and other countries. At data collection in 2023, there were no approved gene therapies for DMD. Using the threshold technique, we assessed the maximum acceptable risk of death (MAR) from non-curative gene therapy with time-limited benefit at different stages of DMD progression. Among 263 participants, mean MAR ranged from 2.4 % (treatment in newborns) to 5.4 % (last year able to lift hands to mouth); risk tolerance increased with advancing disease stages. Significant proportions (22.4 %-32.8 %) were willing to accept MAR >10 %. Reasons for higher MAR included the progressive and severe disease, limited treatment alternatives, and participant-reported expected therapy benefits. Those who demonstrated less risk tolerance described uncertainty, maintaining quality of life, optimism regarding future therapies, and the currently uncertain duration of benefit. There were no significant differences in MAR between caregivers and adults with DMD and between respondents in the U.S. and U.K except in the newborn period, though our small sample size is a limitation. MARs remained relatively stable from 2018 to 2023.
Doğan Arı AB, Türkyılmaz A, Çavdarlı B
… +1 more, Kılıç E
Eur J Med Genet
· 2025 Dec · PMID 41061959
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Kabuki syndrome (KS, #147920) is a rare genetic disorder characterized by postnatal growth deficiency, hypotonia, typical facial features, microcephaly, persistence of fetal fingertip pads, and intellectual disability. I...Kabuki syndrome (KS, #147920) is a rare genetic disorder characterized by postnatal growth deficiency, hypotonia, typical facial features, microcephaly, persistence of fetal fingertip pads, and intellectual disability. It is caused by variants in KMT2D and KDM6A, which encode proteins that regulate gene expression during embryogenesis and growth through histone methylation. This study reports 13 KS patients exhibiting distinct phenotypic features and 13 KMT2D variants, three of which were novel. All the patients exhibited a characteristic facial appearance and prominent fetal pads. Cardiac defects and ophthalmologic findings were present in 11 patients (84 %), renal anomalies in seven (54 %), and hearing loss in six (46 %). Intellectual disability was observed in 11 of 12 patients (91 %). One patient had pilomatricoma and another had ganglioneuroblastoma. In all patients, a diagnosis of Kabuki syndrome was considered based on the characteristic facial and clinical features. Molecular diagnosis was confirmed through KMT2D and KDM6A sequencing and whole exome analysis. This study aimed to describe the clinical and molecular characteristics of KS patients, expand the known KMT2D mutation spectrum, and contribute new clinical and molecular data to the literature. Accurate diagnosis is essential for improving clinical awareness, guiding patient management, and providing genetic counseling to affected families.