Variable Intellectual Disability Research Articles

WDR45 variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females.

Pathogenic variants of WD repeat domain 45 (WDR45) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of WDR45 using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, WDR45 variants accounted for 12% (6/51) of the females with developmental delay, suggesting that WDR45 is a major gene in females with developmental delay. Pathogenic variants of WDR45 result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.

The motivations and methods behind sharing a pediatric Prader-Willi syndrome diagnosis.

Prader-Willi syndrome (PWS) is a genetic condition caused by a lack of paternally-expressed imprinted genes at chromosome 15q11.2-q13 and characterized by hyperphagia, behavioral challenges, and variable intellectual disability. Once a PWS diagnosis is established, sharing diagnosis information with an affected child can be challenging due to its early age of onset and diverse phenotype. This mixed-methods study aimed to evaluate how parents and guardians have shared a PWS diagnosis with their child and examine the motivating and influencing factors behind their disclosure. Parents and guardians of children with PWS aged at least 5 years completed a survey, and a select group completed an interview. A total of 51 surveys and 15 interviews were completed, with the majority of participants (n = 46; 90%) having shared at least some diagnosis information with their child. Parents and guardians were more likely to disclose if they self-reported a higher level of knowledge about PWS (p = 0.004) and if their child is currently older (p = 0.02) and/or has at least one sibling (p = 0.046). Interview analysis revealed 15 themes and 10 subthemes that illustrated parents' motivations, methods, and experiences with disclosure. This research provides information for others considering disclosure of PWS or another rare diagnosis with their child.

Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability

BackgroundPlexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine...

Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis. We describe 42 individuals with protein-truncating variants (PTVs) or (partial) deletions of ZFHX3, exhibiting variable intellectual disability and autism spectrum disorder, recurrent facial features, relative short stature, brachydactyly, and, rarely, cleft palate. ZFHX3 LoF associates with a specific methylation profile in whole blood extracted DNA. Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation. ZFHX3 was found to interact with the chromatin remodeling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex, suggesting a function in chromatin remodeling and mRNA processing. Furthermore, ChIP-seq for ZFHX3 revealed that it predominantly binds promoters of genes involved in nervous system development. We conclude that loss-of-function variants in ZFHX3 are a cause of syndromic ID associating with a specific DNA methylation profile.

Bohring opitz syndrome: a rare case report

Bohring- Opitz syndrome (BOS) first described by Bohring et al in 1999, is a rare congenital disorder of unknown etiology. He described 4 cases with characteristic features. This syndrome is characterized by distinctive facial features and posture, growth failure, variable intellectual disability, and variable anomalies. The diagnosis of BOS is established in a proband with suggestive clinical features and/or Identification of constitutional heterozygous pathogenic variant in ASXL1 by molecular genetic testing. We presented a case which phenotypically and genetically matches the findings of this syndrome.

LHX2 haploinsufficiency causes a variable neurodevelopmental disorder

PurposeLHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date. MethodsThrough international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems. ResultsAffected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction–mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants. ConclusionWe implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.

Precise definition of the breakpoints of an apparently balanced translocation between chromosome 3q26 and chromosome 7q36: Role of KMT2C disruption.

When a de novo balanced reciprocal translocation is identified in the patient, the cause of phenotype of the patient can be explained by detecting the breakpoints of the genes. Here, we report a 3-year-old patient with developmental delay, autism spectrum disorder, and distinctive facial features who had an apparently balanced translocation between chromosome 3q26 and chromosome 7q36. Nanopore long-read sequencing revealed that balanced translocation disrupted the KMT2C gene, the haploinsufficiency of which leads to Kleefstra syndrome 2 characterized by delayed psychomotor development, variable intellectual disability and mild dysmorphism. Nanopore long-read sequencing was shown to be useful in elucidating the exact genetic etiology of patients with nonspecific clinical findings.

Neuroanatomy of dementia in Down Syndrome revealed using a voxel‐based morphometry approach to computed tomography

AbstractBackgroundPeople with Down syndrome (DS) are more likely to develop Alzheimer’s disease than the general population, but comorbidities and variable intellectual disability complicate diagnosis and disease monitoring. Although neuroimaging may help elucidate the pathogenesis of dementia, studies using magnetic resonance imaging (MRI) in DS subjects with dementia are limited due to greater motion artefact in those with severe cognitive impairment. Computed tomography (CT) is faster, thus less impacted by motion, but poor tissue contrast makes analysis of cortical and subcortical changes difficult. In this study, we use CTseg, an algorithm able to robustly spatially normalise and segment CT scans, to analyse grey matter (GM) and white matter (WM) differences in 98 DS subjects with and without cognitive impairment due to dementia.MethodsThe CT scans of 120 DS patients from the Adult Down Syndrome unit at the Hospital Universitario La Princesa were selected. Dementia level was classified by retrospective review of medical records as 0 (cognitively stable), 1 (mild dementia), 2 (moderate dementia), or 3 (advanced dementia) according to the DSM‐V operational criteria. Premorbid functionality was assessed using Part 1 (“Level of ‘best’ ability”) of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). Those with artefacts, faulty scans, or incidental brain findings were excluded, leaving a final sample of 98 subjects (mean age: 48±8.5 years; 45% female; 62 cognitively stable). CT scans were segmented into GM, WM, and cerebrospinal fluid using CTseg (https://github.com/WCHN/CTseg). Voxel‐based morphometry (VBM) analyses were carried out separately on smoothed and modulated GM and WM images, correlating with dementia level whilst controlling for age, sex, DSQIID, and total intracranial volume.ResultsGM volume was significantly negatively correlated with dementia level in the bilateral parahippocampal gyri, extending into hippocampus, and amygdalae. By contrast, significant WM reductions associated with dementia level were primarily parietal and occipitotemporal and right‐lateralised in the superior and inferior longitudinal fasciculi (p<0.001, FWE‐corrected).ConclusionsOur study uses a novel algorithm that allows the analysis of CT scans using VBM methods, enabling the inclusion of a sizeable sample of DS subjects with dementia, a group difficult to study with neuroimaging due to practical constraints.

Neuroanatomy of dementia in Down Syndrome revealed using a voxel‐based morphometry approach to computed tomography

AbstractBackgroundPeople with Down syndrome (DS) are more likely to develop Alzheimer’s disease than the general population, but comorbidities and variable intellectual disability complicate diagnosis and disease monitoring. Although neuroimaging may help elucidate the pathogenesis of dementia, studies using magnetic resonance imaging (MRI) in DS subjects with dementia are limited due to greater motion artefact in those with severe cognitive impairment. Computed tomography (CT) is faster, thus less impacted by motion, but poor tissue contrast makes analysis of cortical and subcortical changes difficult. In this study, we use CTseg, an algorithm able to robustly spatially normalise and segment CT scans, to analyse grey matter (GM) and white matter (WM) differences in 98 DS subjects with and without cognitive impairment due to dementia.MethodsThe CT scans of 120 DS patients from the Adult Down Syndrome unit at the Hospital Universitario La Princesa were selected. Dementia level was classified by retrospective review of medical records as 0 (cognitively stable), 1 (mild dementia), 2 (moderate dementia), or 3 (advanced dementia) according to the DSM‐V operational criteria. Premorbid functionality was assessed using Part 1 (“Level of ‘best’ ability”) of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). Those with artefacts, faulty scans, or incidental brain findings were excluded, leaving a final sample of 98 subjects (mean age: 48±8.5 years; 45% female; 62 cognitively stable). CT scans were segmented into GM, WM, and cerebrospinal fluid using CTseg (https://github.com/WCHN/CTseg). Voxel‐based morphometry (VBM) analyses were carried out separately on smoothed and modulated GM and WM images, correlating with dementia level whilst controlling for age, sex, DSQIID, and total intracranial volume.ResultsGM volume was significantly negatively correlated with dementia level in the bilateral parahippocampal gyri, extending into hippocampus, and amygdalae. By contrast, significant WM reductions associated with dementia level were primarily parietal and occipitotemporal and right‐lateralised in the superior and inferior longitudinal fasciculi (p<0.001, FWE‐corrected).ConclusionsOur study uses a novel algorithm that allows the analysis of CT scans using VBM methods, enabling the inclusion of a sizeable sample of DS subjects with dementia, a group difficult to study with neuroimaging due to practical constraints.

Genetics for the pediatric endocrinologists – 2 Primordial short stature in children and adolescents

Primordial short stature (PSS) is an extremely rare group of monogenic disorders characterized by profound global growth failure commencing in the fetal life and continuing postnatally for the rest of the life. It is suspected when there is an extreme degree of proportionate short stature and global growth failure with or without microcephaly, and without any evidence of known skeletal dysplasia. The cardinal features of PSS include severe intrauterine and postnatal growth failure, severe postnatal short stature, primary microcephaly, characteristic facial features, and variable intellectual disability. The most common genetic etiology is monogenic except for Silver–Russell syndrome, where an epigenetic mechanism is a predominant cause of primordial dwarfism. This review demonstrates a holistic approach to the diagnosis and management of PSS in children and adolescents.

The past, present, and future for constitutional ring chromosomes: A report of the international consortium for human ring chromosomes.

SummaryHuman ring chromosomes (RCs) are rare diseases with an estimated newborn incidence of 1/50,000 and an annual occurrence of 2,800 patients globally. Over the past 60 years, banding cytogenetics, fluorescence in situ hybridization (FISH), chromosome microarray analysis (CMA), and whole-genome sequencing (WGS) has been used to detect an RC and further characterize its genomic alterations. Ring syndrome featuring sever growth retardation and variable intellectual disability has been considered as general clinical presentations for all RCs due to the cellular losses from the dynamic mosaicism of RC instability through mitosis. Cytogenomic heterogeneity ranging from simple complete RCs to complex rearranged RCs and variable RC intolerance with different relative frequencies have been observed. Clinical heterogeneity, including chromosome-specific deletion and duplication syndromes, gene-related organ and tissue defects, cancer predisposition to different types of tumors, and reproductive failure, has been reported in the literature. However, the patients with RCs reported in the literature accounted for less than 1% of its occurrence. Current diagnostic practice lacks laboratory standards for analyzing cellular behavior and genomic imbalances of RCs to evaluate the compound effects on patients. Under-representation of clinical cases and lack of comprehensive diagnostic analysis make it a challenge for evidence-based interpretation of clinico-cytogenomic correlations and recommendation of follow-up clinical management. Given recent advancements in genomic technologies and organized efforts by international collaborations and patient advocacy organizations, the prospective of standardized cytogenomic diagnosis and evidence-based clinical management for all patients with RCs could be achieved at an unprecedented global scale.

Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6.

While inherited hemizygous variants in PHF6 cause X‐linked recessive Borjeson‐Forssman‐Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies. We observed skewed X‐inactivation in blood and streaky skin pigmentation compatible with functional mosaicism. Variants occurred de novo in 10 individuals, of whom one was only mildly affected and transmitted it to her more severely affected daughter. The mutational spectrum comprises a two‐exon deletion, five truncating, one splice‐site and three missense variants, the latter all located in the PHD2 domain and predicted to severely destabilize the domain structure. This observation supports the hypothesis of more severe variants in females contributing to gender‐specific phenotypes in addition to or in combination with effects of X‐inactivation and functional mosaicism. Therefore, our findings further delineate the clinical and mutational spectrum of female BFLS and provide further insights into possible genotype–phenotype correlations between females and males.

Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan.

BackgroundBiallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy.MethodsWe performed whole‐exome sequencing (WES) of DNA samples from 804 Charcot–Marie–Tooth (CMT) cases that could not be genetically diagnosed by DNA‐targeted resequencing microarray using next‐generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features.ResultsWe identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early‐onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis.ConclusionOur study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT‐related gene panel for comprehensive genetic screening, particularly for patients with early‐onset demyelinating CMT.

Rare and de novo duplications containing TCF20 are associated with a neurodevelopmental disorder.

Transcriptor co-activator factor 20 gene (TCF20) encodes a nuclear chromatin-binding protein involved in regulation of gene expression. In human pathology, pathogenic variants or deletions in TCF20 were identified in patients with developmental delay, variable intellectual disability and behavioral impairment (OMIM: 618430). The shared core phenotype includes developmental delay, hypotonia, motor delay, autism spectrum disorders, neurobehavioral anomalies, neurological features such as ataxia, seizures, movement disorders, structural brain anomalies, craniofacial features and various congenital anomalies. Most pathogenic variants are loss-of-function variants. Duplication including TCF20 was suspected to cause a neurodevelopmental disorder (NDD) with mirror traits compared to patients with TCF20 deletions. In the present study, we report three patients from three unrelated families with NDD with a de novo duplication at 22q13.2 encompassing TCF20. We propose that the TCF20 duplication could be involved in a new 22q13.2 microduplication syndrome with high penetrance, enlarging the genotype-phenotype knowledge of TCF20-associated NDDs.

Diagnosis of Shashi-Pena Syndrome Caused by Chromosomal Rearrangement Using Nanopore Sequencing.

Background and ObjectivesThe aim of this study was to uncover the genetic cause of delayed psychomotor development and variable intellectual disability in a proband whose previous genetic analyses, including chromosome microarray and whole exome sequencing, had been negative.MethodsLong-read sequencing Oxford Nanopore Technology and RNA-seq analysis were performed on peripheral blood mononuclear cells. Genes with a fold change ≥ 1.5 and p ≤ 0.05 were identified as differentially expressed.ResultsClinical examinations showed that the proband's features were similar to a rare autosomal-dominant neurodevelopmental syndrome, Shashi-Pena syndrome (MIM #617190). Karyotyping showed that a chromosomal balanced translocation t(2; 11) (p23; q23) was detected in the proband, her father, and her grandmother. Meanwhile, long-read sequencing identified 102 balanced translocations and 145 inversions affecting ASXL2 at an average of 15×. Combined with the family's RNA-seq results, the average mRNA expression of ASXL2 decreased in the patients.DiscussionWe identified a complex chromosomal rearrangement affecting ASXL2 as a pathogenic mechanism of Shashi-Pena syndrome in a Chinese family. This case study suggests that nanopore sequencing is suitable for pathogenic analysis of complex rearrangements, providing new avenues for the diagnosis of genetic diseases.

GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome

BackgroundIdentification and characterisation of monogenic causes of complex neurological phenotypes are important for genetic counselling and prognostication. Bi-allelic pathogenic variants in the gene encoding GLRX5, a protein involved in the early steps of Fe-S cluster biogenesis, are rare and cause two distinct phenotypes: isolated sideroblastic anemia and a neurological phenotype with variant non-ketotic hyperglycinemia. In this study, we analysed the evolution of clinical and MRI findings and long-term outcome of patients with GLRX5 mutations.MethodsFour patients from three Australian families of Lebanese descent were identified. All patients presented in childhood and were followed up into adult life through multiple clinical assessments. All were prescribed sodium benzoate.ResultsAll patients (all females, age range 18–56 years) showed a complex neurological phenotype characterised by varying combinations of spastic paraparesis, length-dependent motor/sensory-motor axonal polyneuropathy, and psychiatric disturbances with variable intellectual disability. All had non-ketotic hyperglycinemia and a homozygous pathogenic c.151_153delAAG (p.K51del) change in GLRX5. Motor disability gradually progressed reaching moderate disability during adolescence and moderately severe disability during adult life. The major MRI finding was the upper cervical spinal cord signal changes with contrast enhancement noted in all and additional leukoencephalopathy in one. On follow up MRI, the white matter lesions diminished on a subsequent scan and then remained static over time. The spinal cord showed gliotic changes. Two patients have previously demonstrated low pyruvate dehydrogenase complex deficiency but none had plasma lactate elevation, nor biochemical evidence of branch-chain keto-dehydrogenase deficiency. Glycine levels reduced in patients that tolerated sodium benzoate, possibly stabilising clinical manifestations.ConclusionsThis report demonstrates that the p.K51del GLRX5 variant causes a distinct and predictable neurological phenotype. The clinical assessments spanning from childhood to adult life enable physicians to infer the natural history of GLRX5 related neurological disorder. There may be widespread metabolic consequences, and optimal management is unknown.

Current Approaches to Improve Balance in Down Syndrome Population-A Systematic Review

Down syndrome is one of the most common chromosomal disorders in pediatrics characterized by variable intellectual disability, generalized joint laxity, and hypotonia that compromises their function and causes a delay in developing gross motor skills, poor balance, and coordination. Thus, this study aims to determine the current yet effective treatment approaches to improve balance in the Down syndrome population. The studies were explored across seven electronic databases that include MEDLINE, PubMed, Cochrane Library, Google Scholar, Scopus, PEDro, and Web of Science from inception till October 2020 comprised of experimental studies published in English language investigating the effects on balance in children and adults diagnosed with DS considering different interventions. A total of 1,570 records were retrieved from seven electronic databases published between the year's tenure of 2013-2020. 144 full-text papers were extracted to be reviewed, of which only 18 experimental studies were selected on the basis of inclusion criteria that involved 493 Down syndrome patients, investigated the effects of therapeutic exercises, manual therapy techniques, and patient-related instructions on standardized balance scales/tests. It was concluded that all the included trials demonstrated significantly profound effects in improving the static and dynamic balance of Down syndrome patients. Therefore, none of the interventions is declared as superior to another in terms of obtained results. Furthermore, these diverse interventions need to be investigated more for better understating and generalizability of outcomes.

EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum

BackgroundAn identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.Results21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation.ConclusionsOur study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.

De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with denovo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.

Clinical utility of genetic testing in the early diagnosis of Danon disease mimicking hypertrophic cardiomyopathy: a case report

BackgroundDanon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features.This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life.Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis.Case presentationHere, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease.ConclusionsThis report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.