Eur J Med Genet [JOURNAL]
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200 papers
New insights into the complex genetic architecture of age-related hearing loss.
Bonnet C, Aiche S, Boucher S
Eur J Med Genet · 2026 Jul · PMID 42379497 · Publisher ↗
Age-related hearing loss (ARHL), or presbycusis, is a very common sensory disorder resulting from cumulative exposure to environmental factors, biological aging and a significant genetic component. Although most cases of...
Age-related hearing loss (ARHL), or presbycusis, is a very common sensory disorder resulting from cumulative exposure to environmental factors, biological aging and a significant genetic component. Although most cases of ARHL result from the combined influence of numerous low-effect variants, the increasing number of monogenic forms has shown the importance of rare, highly penetrant mutations in ARHL. Advances in whole-exome and whole-genome sequencing have strengthened the evidence for monogenic contributions, identifying deleterious variants consistent with dominant, recessive, or mitochondrial inheritance patterns. These monogenic cases provide valuable insights into the molecular mechanisms underlying cochlear aging and the vulnerability of sensory cells. To date, several genes have been clearly identified as responsible for familial or sporadic late-onset hearing loss, including KCNQ4, GRHL2, ILDR1, EYA4, MYO6, MYO7A, TECTA, WFS1, CDH23, and TMC1. Mutations in these genes affect diverse biological pathways such as potassium recycling, epithelial integrity, transcriptional regulation, mechanotransduction, extracellular matrix stability, and hair cell maintenance-functions that are fundamental to the long-term preservation of hearing. It is important to note that there is a growing overlap between the genes involved in Mendelian deafness and the susceptibility loci identified in ARHL, suggesting the existence of common molecular mechanisms between early-onset hereditary deafness and some forms of progressive ARHL. Furthermore, new data highlight the role of epigenetic regulation, mitochondrial dysfunction, cochlear synaptopathy, and non-coding RNAs in hearing loss. Despite major advances, several challenges remain, including phenotypic heterogeneity, limited representation of non-European populations, and a lack of consistency in the reproducibility of results across studies. Distinguishing between subtypes of ARHL characterized by audiometry-including sensory, neural and synaptopathic, metabolic forms, will likely be essential for improving genetic analyses and precision medicine approaches. Moreover, although polygenic risk scores (PRS) represent a promising strategy for risk prediction, their clinical applicability remains limited. Overall, the integration of monogenic, polygenic, environmental, and epigenetic data will be essential for understanding the complex genetic architecture of ARHL and for developing future personalized therapeutic interventions.
Clinical and genetic spectrum of trichorhinophalangeal syndrome type I/III in 20 children of Korean origin.
Park A, Choi N, Cho TJ … +1 more , Ko JM
Eur J Med Genet · 2026 Jun · PMID 42361898 · Publisher ↗
BACKGROUND: Trichorhinophalangeal syndrome type I/III (TRPS I/III) is a rare autosomal dominant skeletal dysplasia caused by pathogenic variants of TRPS1. Although several European cohorts have been reported, data from E...
BACKGROUND: Trichorhinophalangeal syndrome type I/III (TRPS I/III) is a rare autosomal dominant skeletal dysplasia caused by pathogenic variants of TRPS1. Although several European cohorts have been reported, data from East Asian populations remain limited and longitudinal growth patterns and treatment responses have not been systematically evaluated. METHODS: We conducted a retrospective single-center study of 20 unrelated children of Korean origin with molecularly confirmed TRPS I/III, between 2012 and 2024. The clinical, radiological, and genetic data were reviewed. Growth parameters were analyzed using Korean reference standards and genotype-phenotype correlations were explored. Treatment responses to recombinant human growth hormone (rhGH) and minoxidil were assessed descriptively. RESULTS: All the patients exhibited characteristic craniofacial features and cone-shaped epiphyses with variable skeletal involvement. Short stature (standard deviation score [SDS] of height < -2) was observed in 21% of patients. Bone age was delayed before 12 years of age but showed rapid advancement thereafter, accompanied by a decline in height SDS during adolescence (p = 0.017). Truncating variants were identified in 65% of patients, missense variants in exon 6 in 15%, and exonic deletions in 20%. Missense variants in exon 6 were consistently associated with severe brachydactyly, whereas the overall stature showed no clear correlation with genotype. Responses to rhGH and minoxidil treatments were variable. CONCLUSIONS: TRPS I/III demonstrated substantial phenotypic heterogeneity and age-dependent growth dynamics in this Korean cohort. Severe distal limb involvement was associated with exon 6 missense variants, whereas growth impairment remained variable. Long-term follow-up and multidisciplinary management are essential to optimize clinical outcomes.
Hearing outcomes after cochlear implantation in two patients with ATP6V1B2-related deafness and onychodystrophy.
Chamieh S, Marzin P, Achard S … +6 more , Blanc P, Jonard L, Battelino S, Trebusak K, Serey-Gaut M, Marlin S
Eur J Med Genet · 2026 Jun · PMID 42361897 · Publisher ↗
The gold standard recommendation for congenital sensorineural hearing loss (SNHL) care is cochlear implantation (CI). Adjusting for confounding factors such as developmental comorbidities is crucial when assessing expect...
The gold standard recommendation for congenital sensorineural hearing loss (SNHL) care is cochlear implantation (CI). Adjusting for confounding factors such as developmental comorbidities is crucial when assessing expected outcomes of the procedure for the patients, their families, and their medical teams. We describe two clinical cases of the deafness and onychodystrophy (DOD) spectrum and the benefit of molecular diagnosis to underline the importance of genetic testing when evaluating potential CI outcomes in syndromic congenital SNHL.
A novel de novo CACNA1G variant p.(Arg1553Gln) associated with neurodevelopmental delay and cerebellar hypoplasia: Expanding the phenotypic spectrum.
Selek A, Orpay F, Unay B
Eur J Med Genet · 2026 Jun · PMID 42309484 · Publisher ↗
CACNA1G encodes the Cav3.1 T-type calcium channel, a key regulator of neuronal excitability and thalamocortical rhythmicity. Pathogenic variants have been associated with neurodevelopmental disorders, frequently accompan...
CACNA1G encodes the Cav3.1 T-type calcium channel, a key regulator of neuronal excitability and thalamocortical rhythmicity. Pathogenic variants have been associated with neurodevelopmental disorders, frequently accompanied by epilepsy and cerebellar abnormalities. We report a patient with global developmental delay and autism spectrum disorder who developed progressive gait instability and was found to harbor a novel de-novo CACNA1G variant, c.4658G > A p.(Arg1553Gln). Notably, the patient had no history of seizures and normal electroencephalographic findings. Brain magnetic resonance imaging revealed cerebellar and vermian hypoplasia, consistent with previously described cases, as well as an incidental intracranial lipoma. Distinctive clinical features included macrocephaly and appendicular hypertonia, findings not previously reported in association with CACNA1G-related disorders and potentially expanding the phenotypic spectrum. The identified variant is located in the intracellular III-IV linker region of Cav3.1, outside the canonical pore-forming domains where most epilepsy-associated variants cluster. Its absence from the literature and public variant databases supports its novelty. This case broadens the clinical and molecular spectrum of CACNA1G-related disease and highlights phenotypic variability, particularly in patients without epilepsy.
Development of a predictive matrix for pre-test genetic counselling in inherited retinal diseases based on data from 1001 patients enrolled in the IRD-PT registry.
Figueiredo I, Cruz N, Gaspar B … +6 more , Gouveia N, Martins PM, Geada S, Silva R, Carvalho AL, Marques JP
Eur J Med Genet · 2026 Jun · PMID 42302894 · Publisher ↗
Genetic testing plays a pivotal role in the management of Inherited Retinal Diseases (IRDs), yet a significant proportion of patients remain without a molecular diagnosis. This study aimed to develop a predictive matrix...
Genetic testing plays a pivotal role in the management of Inherited Retinal Diseases (IRDs), yet a significant proportion of patients remain without a molecular diagnosis. This study aimed to develop a predictive matrix to estimate the likelihood of diagnostic success in order to manage patient expectations prior to genetic testing. Conducted as a retrospective, single-center cohort study, it analyzed data from 1001 IRD patients across 804 unrelated families enrolled in the IRD-PT registry. Key clinical variables-including age at symptom onset, family history, consanguinity, and referral timing-were evaluated for their association with genetic diagnostic yield. Results showed that 68.03% of families received a solved diagnosis, while 11.19% were likely solved. The presence of consanguinity, a positive family history, or childhood symptom onset significantly increased the probability of a solved diagnosis (up to 81.7%), whereas their absence reduced it to 31.2%. The study culminated in the creation of a conditional probability model that stratifies patients by their likelihood of molecular confirmation. This tool offers clinicians a practical, evidence-based approach to pre-test genetic counselling, enhancing transparency and expectation management for patients undergoing IRD genetic testing.
Genotype before phenotype? Reversing the diagnostic odyssey in genomic medicine.
Chebly A, El Shamieh S
Eur J Med Genet · 2026 Jun · PMID 42235818 · Publisher ↗
For decades, the diagnosis of rare genetic disorders has relied on a phenotype-driven approach, often resulting in a prolonged "diagnostic odyssey." The widespread use of whole-exome and whole-genome sequencing has trans...
For decades, the diagnosis of rare genetic disorders has relied on a phenotype-driven approach, often resulting in a prolonged "diagnostic odyssey." The widespread use of whole-exome and whole-genome sequencing has transformed this paradigm, increasingly enabling genotype-first diagnoses before a clear clinical phenotype is recognized. This shift may contribute to a reversal of the diagnostic odyssey, in which genetic findings guide subsequent clinical evaluation through reverse phenotyping. Large-scale biobank studies and newborn genomic screening programs are further accelerating this paradigm shift. Although this approach has improved diagnostic yield, it also introduces interpretative challenges, including the risk of phenotype reinterpretation bias and the persistent burden of variants of uncertain significance (VUS), particularly when genetic variants only partially explain the clinical presentation. This article discusses the emergence of genotype-driven diagnosis and emphasizes the need for balanced integration of genomic and clinical data in modern precision medicine.
A multi-omics approach to characterize a deep intronic ARID1A deletion in Coffin-Siris syndrome.
Schuhmann S, Bosch E, Fink A … +13 more , Schüssler S, Uebe S, Wiesener A, Ekici AB, Alders MM, Popp B, Kerkhof J, Brockmann EM, Sadikovic B, Rompel O, Trollmann R, Reis A, Vasileiou G
Eur J Med Genet · 2026 May · PMID 42173440 · Publisher ↗
Pathogenic variants in BAF complex genes are linked to neurodevelopmental disorders, termed BAFopathies. Coffin-Siris syndrome (CSS) is the most well-defined BAFopathy caused by variants in several BAF subunit genes. ARI...
Pathogenic variants in BAF complex genes are linked to neurodevelopmental disorders, termed BAFopathies. Coffin-Siris syndrome (CSS) is the most well-defined BAFopathy caused by variants in several BAF subunit genes. ARID1A variants are responsible for 6-8% of CSS cases. We report a female individual with clinical and phenotypic manifestations suggestive of CSS. Trio exome sequencing failed to identify a causative variant. Short-read genome sequencing revealed a de novo 24 kb intronic deletion in ARID1A. Methylation analysis showed a BAFopathy-like profile supporting pathogenicity. Transcriptome analysis and RT-PCR detected a rare aberrant splicing event in a subset of ARID1A transcripts: the activation of a pseudoexon, resulting in a premature termination codon as the underlying pathomechanism. This is the first non-coding pathogenic alteration reported in ARID1A and the second in a CSS gene. This case highlights how the combination of genomic, transcriptomic and epigenomic data is crucial to improve diagnostic accuracy in unsolved cases.
Novelty and idiosyncrasy: the clay feet of rare disease descriptions.
Aouchiche K, Guerry P, Fabre A
Eur J Med Genet · 2026 May · PMID 42167721 · Publisher ↗
Medical understanding of rare diseases is hindered by incomplete initial descriptions. A related but often overlooked question is how many patients are required to define a phenotype. We evaluated the phenome coverage of...
Medical understanding of rare diseases is hindered by incomplete initial descriptions. A related but often overlooked question is how many patients are required to define a phenotype. We evaluated the phenome coverage of 10 recently published gene-disease associations using the Human Phenotype Ontology (HPO) system as a template and calculated the sample sizes required to significantly associate the prevalence of a given trait with particular phenotype. The phenome coverage of the studied descriptions was below 50% in all cases (range 4 to 43%, median, 26%) and the number of patients described (median, 3; range 1 to 17 patients) was insufficient to establish all but very strong associations (relative risks >5). These results highlight the importance of thorough phenotyping on the one hand, and of continued publication of case reports on the other, even after a disease is thought to be well known.
VPS35L-related Ritscher-Schinzel syndrome: Expanding genotype-phenotype correlations.
Carelli I, Rondot F, Luca M … +10 more , Reynolds G, Massuras S, Di Gregorio E, Marinoni R, Papagni G, D'Alfonso S, Colavito D, Patanè A, Brusco A, Mussa A
Eur J Med Genet · 2026 May · PMID 42144185 · Publisher ↗
INTRODUCTION: Ritscher-Schinzel syndrome (RTSC; 3C syndrome) is a rare syndromic neurodevelopmental disorder resulting from defects in endosomal recycling. Biallelic variants in VPS35L, encoding a core component of the R...
INTRODUCTION: Ritscher-Schinzel syndrome (RTSC; 3C syndrome) is a rare syndromic neurodevelopmental disorder resulting from defects in endosomal recycling. Biallelic variants in VPS35L, encoding a core component of the Retriever complex, have only recently been implicated in RTSC. METHODS: Trio-based-whole exome sequencing was performed in a male infant with classical RTSC features. Variant pathogenicity was assessed using population databases, multiple in-silico predictors, structural modeling, and splicing analyses. Segregation analysis was performed in the parents. RESULTS: A novel homozygous VPS35L variant (NM_020314.7: c.881T > C; p.(Phe294Ser)) affecting a highly conserved residue was identified. The variant is absent from population databases and is predicted to be deleterious. Structural modeling and stability calculations indicate a marked destabilizing effect, whereas splicing predictions do not support a major effect of nucleotide change on canonical splice site usage. Clinically, the patient exhibited cerebellar, craniofacial, skeletal, and cardiac anomalies with severe postnatal growth retardation. CONCLUSIONS: This patient provides additional evidence supporting the pathogenic role of VPS35L in RTSC and expands the emerging molecular and clinical spectrum of VPS35L-related disorder, highlighting the value of detailed genotype-phenotype correlation in ultra-rare syndromes.
Child-onset hepatic glycogenosis and steatosis in PTEN-related disorder.
Sihaklang B, Vaseenon H, Lertudomphonwanit C … +4 more , Sornmayura P, Getsuwan S, Treepongkaruna S, Wattanasirichaigoon D
Eur J Med Genet · 2026 May · PMID 42106060 · Publisher ↗
Bannayan-Riley-Ruvalcaba syndrome is a rare PTEN-related disorder characterized by macrocephaly, intellectual disability, autism, hamartomatous intestinal polyps, and pigmentation of the glans penis. We describe a novel...
Bannayan-Riley-Ruvalcaba syndrome is a rare PTEN-related disorder characterized by macrocephaly, intellectual disability, autism, hamartomatous intestinal polyps, and pigmentation of the glans penis. We describe a novel pathogenic variant of PTEN, c.48del (p.Gln17LysfsTer7), along with the first description of hepatic glycogenosis and steatosis in a child with BRRS. We proposed that the mutation likely led to a release of the inhibition of the insulin signaling pathway in the liver, leading to increased glycogen production and de novo synthesis of fatty acids, as previously shown in mice. Our data further extend possible metabolic complications of PTEN-related disorder.
MMP13-related Metaphyseal anadysplasia type 1 presenting with rickets-like manifestations in a family.
Thunström S, Antonsson P, Stenberg S … +2 more , Aspholm EE, Swolin Eide D
Eur J Med Genet · 2026 May · PMID 42069302 · Publisher ↗
BACKGROUND: Metaphyseal anadysplasia 1, which includes Spondyloepimetaphyseal dysplasia Missouri type, is a rare autosomal dominant skeletal dysplasia characterized by short stature, mild limb deformities, and transient...
BACKGROUND: Metaphyseal anadysplasia 1, which includes Spondyloepimetaphyseal dysplasia Missouri type, is a rare autosomal dominant skeletal dysplasia characterized by short stature, mild limb deformities, and transient metaphyseal irregularities that typically resolve with age. The condition is caused by heterozygous missense variants in the MMP13 gene, encoding matrix metalloproteinase 13, a key enzyme in endochondral ossification and extracellular matrix remodeling. Pathogenic variants in MMP13 are exceedingly rare, with only a few families reported. CASE PRESENTATION: We report two siblings, aged 3 and 1 years, in Sweden, presenting with clinical and radiological features consistent with Metaphyseal anadysplasia 1. Their father, of Syrian origin, exhibited short stature and mild femoral bowing. Genetic analysis revealed a novel heterozygous missense variant c.217T > C, p.(Ser73Pro) in MMP13, inherited from the affected father, and located within the same MMP13 domain as previously reported patients. The family pedigree demonstrates multiple affected individuals with short stature and bowed femurs, consistent with autosomal dominant inheritance. Radiographic imaging of father confirmed persistent but mild skeletal abnormalities. CONCLUSION: This report expands the genotypic spectrum of Metaphyseal anadysplasia 1 and suggests a putative mutational hotspot in exon 2. It further emphasizes the importance of thorough clinical, radiological, and genetic evaluation in families with short stature and metaphyseal irregularities and a clinical long-term follow-up is proposed with regular radiographic monitoring.
COL12A1-related myopathic Ehlers-Danlos syndrome with Chiari I malformation: A clinical report.
Shinmi J, Takizawa H, Saito Y … +5 more , Matsui A, Oya Y, Sakuta R, Nishino I, Takahashi Y
Eur J Med Genet · 2025 Dec · PMID 42046911 · Publisher ↗
Myopathic Ehlers-Danlos syndrome (mEDS) is a rare connective tissue disorder caused by pathogenic variants in COL12A1. It is characterized by congenital muscle hypotonia, muscle atrophy, and age-related improvement. We r...
Myopathic Ehlers-Danlos syndrome (mEDS) is a rare connective tissue disorder caused by pathogenic variants in COL12A1. It is characterized by congenital muscle hypotonia, muscle atrophy, and age-related improvement. We report the first detailed adult patient of mEDS with a novel compound heterozygous COL12A1 variant, complicated by Chiari I malformation and hydrocephalus. The patient presented with neonatal hypotonia, delayed motor milestones, scoliosis, and joint hypermobility, yet achieved independent ambulation. Muscle biopsy and immunostaining revealed markedly decreased levels of collagen XII. RNA sequencing demonstrated near absence of the long isoform and residual expression of the short isoform, potentially underlying the patient's clinical improvement. This is the first report to clarify the mechanism of preserved motor function in mEDS using RNA sequencing and immunostaining. Chiari I malformations may help distinguish mEDS from COL6-related disorders.
Reflex sympathetic dystrophy-like unilateral erythema caused by a germline SCN9A variant.
Nakato D, Komatsu R, Ono I … +5 more , Misu K, Nakano S, Goto Y, Miya F, Kosaki K
Eur J Med Genet · 2026 May · PMID 41997215 · Publisher ↗
Reflex sympathetic dystrophy (RSD), currently categorized within the spectrum of complex regional pain syndrome (CRPS), is typically considered an acquired disorder characterized by disproportionate pain, erythema, and a...
Reflex sympathetic dystrophy (RSD), currently categorized within the spectrum of complex regional pain syndrome (CRPS), is typically considered an acquired disorder characterized by disproportionate pain, erythema, and autonomic changes. In contrast, inherited erythromelalgia is a genetic pain disorder most often caused by gain-of-function variants in SCN9A encoding the Nav1.7 sodium channel and usually presents with bilateral, symmetric distal limb pain and redness. Here, we describe a multigenerational family with a strictly unilateral, trauma-triggered neurovascular pain phenotype associated with a previously unreported heterozygous germline SCN9A variant (c.4784T > G, p. Leu1595Arg). Affected individuals experienced episodic attacks in which minor mechanical or physiological stimuli induced progressive unilateral erythema, warmth, and severe pain spreading from the site of injury and sharply demarcated at the midline, without contralateral involvement. Attacks lasted hours to nearly one day and tended to decrease with age. The variant was absent from population databases and co-segregated with the phenotype within the family, fulfilling ACMG/AMP criteria for likely pathogenicity. The consistent unilateral distribution cannot be explained by mosaicism and is instead compatible with activation of ipsilateral segmental nociceptive and neurovascular reflex circuits that function largely independently across the spinal midline. We propose that excessive positive feedback between C-fiber activation and axon reflex-mediated neurogenic inflammation underlies attack propagation and duration. This framework also suggests therapeutic benefit from agents that interrupt activity-dependent transmitter release, such as gabapentinoids. These findings expand the phenotypic spectrum of SCN9A-related pain disorders and provide a genetically anchored model for unilateral RSD/CRPS-like neurovascular pain.
Phenotypic discordance in monozygotic twins with a CDH2 variant.
Hansman L, Galan-Cadena J, Bartlett V … +6 more , Goldring G, Mitchell T, Mittag D, Prosnitz A, Macaya D, Baker EK
Eur J Med Genet · 2026 May · PMID 41997214 · Publisher ↗
Monoallelic pathogenic variants consistent with Mendelian inheritance patterns causing congenital heart disease (CHD) have been increasingly identified as genetic testing, including genome sequencing (GS), has become mor...
Monoallelic pathogenic variants consistent with Mendelian inheritance patterns causing congenital heart disease (CHD) have been increasingly identified as genetic testing, including genome sequencing (GS), has become more widely available within the clinical space. Here, we focus on a newly described pathogenic variant in CDH2 resulting in Agenesis of Corpus Callosum (ACC), Cardiac, Ocular, and Genital Syndrome (ACOGS). While previous studies document variable expressivity of the CDH2 variants in unrelated individuals, no cases have described such variable expressivity in twins with the same CDH2 variant. We present a novel case of likely monozygotic twins who both carried the same pathogenic CDH2 variant yet exhibited a spectrum of CHD with one presenting with hypoplastic left heart syndrome and the other with ventricular septal defect and pulmonary hypertension.
STAT3 dominant negative Hyper-IgE syndrome: A patient report with actionable genomic findings.
Bloom AS, Amendola LM, Reynolds-Lallement N … +4 more , Urban A, Freeman AF, Walkiewicz MA, Similuk MN
Eur J Med Genet · 2026 May · PMID 41985740 · Full text
Over the last two decades, diagnostic genetic testing for inborn errors of immunity has primarily relied on gene panel-based approaches organized by phenotype. In this report, we describe a patient with a clinical and mo...
Over the last two decades, diagnostic genetic testing for inborn errors of immunity has primarily relied on gene panel-based approaches organized by phenotype. In this report, we describe a patient with a clinical and molecular diagnosis of STAT3 dominant negative hyper-IgE syndrome referred to the National Institutes of Health for further evaluation including genome sequencing. Genome sequencing analysis included primary, secondary, and pharmacogenomic findings. This analysis confirmed the primary molecular diagnosis of STAT3 dominant negative hyper-IgE syndrome and found a pathogenic variant in the LDLR gene associated with familial hypercholesterolemia, which led to the identification of borderline high LDL-C levels in the patient. Additionally, this analysis identified pharmacogenomic genotypes associated with suboptimal therapeutic effects for the frontline treatments of the patient's conditions. Specifically, the patient was found to be a rapid metabolizer of voriconazole, a treatment for severe fungal infections, and to have an increased risk for myopathy induced by taking statins, the most common treatment for familial hypercholesterolemia. This case underscores the potential clinical utility of comprehensive genomic evaluation for patients with rare diseases. The untargeted nature of genome sequencing and broad range of potential findings can inform treatment decisions, shorten the diagnostic odyssey, and enable a more personalized approach to patient care.
Letter to the editor: Comment on "Involvement of cranial nerves in ATTR Ile127Val amyloidosis" by Silva Batista JAD et al. (Eur J Med Genet. 2022 Jul;65(7):104524) and report of 3 new patients.
Rodrigues CL, Brito LA, Freitas HC
Eur J Med Genet · 2026 May · PMID 41887457 · Publisher ↗
Cranial nerve involvement in hereditary transthyretin amyloidosis (ATTRv) remains an underrecognized manifestation, particularly in carriers of atypical variants. Silva Batista et al. (2022) expanded the phenotypic spect...
Cranial nerve involvement in hereditary transthyretin amyloidosis (ATTRv) remains an underrecognized manifestation, particularly in carriers of atypical variants. Silva Batista et al. (2022) expanded the phenotypic spectrum of the p.Ile127Val mutation by reporting cranial neuropathies in approximately 21% of p.Ile127Val individuals. Motivated by these findings, we conducted a retrospectively analysis of our cohort of p.Ile127Val carriers followed at the Neuromuscular/Peripheral Neuropathies Unit of Hospital Geral de Fortaleza, Ceará, Brazil. This hospital is located in the same northeastern region where the original cases were first described. Among 31 p.Ile127Val carriers evaluated up to May 2025, three patients (10%) exhibited some kind of cranial nerve involvement, at a median age of 61 years, which is approximately 10 years later than previously reported. All 3 affected individuals presented with some degree of axonal peripheral neuropathy, but cardiac involvement was observed in only one case. Cranial manifestations appear to be more common in p.Ile127Val carriers than individuals with other ATTRv variants or than the same variant from other regions, which suggests the existence of a potential regional founder effect. Proposed mechanisms include amyloid fibril deposition, inflammation, fibrosis, ischemic injury to cranial nerve vasculature, and, more recently, leptomeningeal amyloid infiltration. Our findings corroborate those of Silva Batista JAD et colleagues and reinforce the importance of distinguishing ATTRv amyloidosis from bulbar motor neuron disease. Recognizing associated features such as sensory axonal neuropathy and dysautonomia in order to ensure timely intervention, which can significantly modify disease progression.
Horizontal gaze palsy with progressive scoliosis (HGPPS): expanding ROBO3 molecular spectrum and refining clinical-neuroimaging phenotypes.
Shams Nosrati MS, Romano F, Dostmohammadi A … +13 more , Traverso M, Nemati AH, Madia F, De Marco P, Doustmohammadi M, Iacomino M, Tavassol ZH, Boogari M, Khorasanian R, Omrani MD, Zara F, Scala M, Capra V
Eur J Med Genet · 2026 May · PMID 41881248 · Publisher ↗
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder caused by biallelic ROBO3 variants, characterized by congenital horizontal gaze restriction, early-onset scoliosis, and dist...
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder caused by biallelic ROBO3 variants, characterized by congenital horizontal gaze restriction, early-onset scoliosis, and distinctive hindbrain malformations. We report two pediatric Patients and integrate current evidence to expand the ROBO3 variant spectrum and refine phenotypic delineation. Detailed clinical evaluation was combined with whole-spine radiography and high-resolution brain MRI with diffusion tensor imaging. Trio-based exome sequencing identified three ROBO3 variants, interpreted according to ACMG/AMP criteria. A novel splice-region variant was evaluated using SpliceAI and Pangolin, while AlphaFold2 modeling and ThermoMPNN, DDMut, SIFT, PolyPhen-2, and ClinPred were used to assess a missense variant affecting the Ig-like domain. Both patients exhibited congenital horizontal gaze palsy, early-onset scoliosis, and the characteristic HGPPS hindbrain triad. Patient #1 carried compound heterozygous variants p.(Arg703Pro) and c.2073+4A > G, while Patient #2 harbored the homozygous p.(Arg245Trp) variant. Literature review confirmed a uniform neuroimaging signature despite variable clinical severity. These findings expand the molecular landscape of HGPPS and underscore the importance of early neuroimaging recognition and orthopedic surveillance in the absence of robust genotype-phenotype correlations.
Genetic and clinical insights into pontocerebellar hypoplasia: Identification of novel variants in an Iranian cohort.
Rezaei Z, Emami F, Heidari M … +6 more , Mohammadi M, Yousefian M, Badv RS, Kowkabi S, Mahdieh N, Ashrafi MR
Eur J Med Genet · 2026 May · PMID 41825724 · Publisher ↗
Pontocerebellar hypoplasia (PCH) comprises a group of rare neurodevelopmental disorders characterized by prenatal-onset cerebellar and pontine atrophy, often leading to severe motor and cognitive impairments. While advan...
Pontocerebellar hypoplasia (PCH) comprises a group of rare neurodevelopmental disorders characterized by prenatal-onset cerebellar and pontine atrophy, often leading to severe motor and cognitive impairments. While advances in genetic diagnostics have improved our understanding, the full spectrum of causative mutations remains unclear, particularly in underrepresented populations. This study aims to delineate the clinical and genetic characteristics of Iranian patients with PCH. We conducted comprehensive clinical evaluations, brain imaging, and laboratory tests, followed by whole-exome sequencing (WES) in Iranian patients with PCH to establish genotype-phenotype correlations. In silico structural and modeling analyses were performed to assess the impact of novel variants on protein function. Ten unrelated patients were diagnosed with different PCH subtypes. Microcephaly and spasticity were observed in 80% of cases, while hypotonia, psychomotor retardation, and speech problems were present in all patients. Additional features included nystagmus (40%), ataxia (20%), decreased deep tendon reflexes (50%), respiratory insufficiency (10%), feeding difficulties (30%), scoliosis (10%), cognitive deficits (20%), seizures (40%), and vision problems (10%). Genetic analysis identified eight pathogenic variants, including four reported mutations in RARS2, EXOSC3, and TSEN54, and four novel mutations in SEPSECS, and RARS2. A recurrent missense variant (EXOSC3: c.395 A > C) was detected in 40% of cases. This study expands the mutational spectrum of PCH by identifying novel variants and underscores the disorder's genetic heterogeneity. The clinical manifestations ranged from mild developmental delay to severe neurodevelopmental decline with respiratory insufficiency and seizures. Our findings provide valuable insights into genotype-phenotype correlations, facilitating early diagnosis and personalized management strategies. Additionally, these results contribute to genetic counseling and future functional studies to elucidate disease mechanisms.
SPIN4-related X-linked overgrowth in a family.
Põlluaas L, Lilles S, Peet A … +5 more , Jee YH, Murumets Ü, Ilisson M, Lintrop M, Õunap K
Eur J Med Genet · 2026 May · PMID 41780720 · Publisher ↗
Spindlin Family Member 4 (SPIN4) is an epigenetic reader gene on the X chromosome. Its loss-of-function variant altering the WNT/β-catenin pathway was recently reported to cause a SPIN4-associated overgrowth syndrome in...
Spindlin Family Member 4 (SPIN4) is an epigenetic reader gene on the X chromosome. Its loss-of-function variant altering the WNT/β-catenin pathway was recently reported to cause a SPIN4-associated overgrowth syndrome in an extended family. The index case is a 14-year-old male with tall stature (+2.0 SD) as the only growth-related finding, accompanied by protruding joints, splenomegaly, low bone mineral density, and normal intelligence. Exome sequencing identified the same loss-of-function variant of SPIN4 (NM_001012968.3:c.312_313del:p.(Arg104Serfs*24)), which was identified in the original family. The variant was present in the proband's mother and maternal grandmother. They both had skewed X-deviation (80% and 20%) and no height gain to their mid-parental heights. The first patient with the same SPIN4 variant described by Lui et al. had more pronounced birth weight and height compared to our patient, and an advanced bone age by one year. Both patients exhibited tall stature, normal pubertal timing, psychomotor development, and intellect, as well as similar facial features and organomegaly (Lui et al., 2023).
Intrafamilial variability of myoclonic dystonia in a large French family carrying a novel SGCE variant.
Popescu C
Eur J Med Genet · 2026 May · PMID 41780719 · Publisher ↗
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.
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