Cardiomyopathy and sudden cardiac death as a rare presentation of mucolipidosis type III in a family with compound heterozygous variants in GNPTAB

Cardiomyopathy and sudden cardiac death as a rare presentation of mucolipidosis type III in a family with compound heterozygous variants in GNPTAB | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Cardiomyopathy and sudden cardiac death as a rare presentation of mucolipidosis type III in a family with compound heterozygous variants in GNPTAB Natalie Stewart, Natasha Henden, Carlos Smith-Diaz, Jennifer Rigby, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8674450/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Homozygous or compound heterozygous loss-of-function variants in GNPTAB cause mucolipidosis type II/III, a progressive multisystem disorder characterized by skeletal abnormalities, short stature, coarse facial features and cardiorespiratory disease. ML III is milder, with an older age of onset and a less severe phenotype. We report two siblings with arrhythmogenic cardiomyopathy and ventricular arrhythmias with compound heterozygous variants in GNPTAB. Methods and Results: The family presented due to the sudden cardiac death of a male in his early 30’s with arrhythmogenic cardiomyopathy identified at autopsy. His sister was found to have cardiomyopathy and experienced a ventricular tachycardia storm. Both siblings had history of skeletal dysplasia first investigated during adolescence. Clinical genetic testing did not identify a cause for the cardiomyopathy, and they were enrolled in the Elusive Hearts study. Following whole genome sequencing, we detected a heterozygous frameshift variant, NM_024312.5( GNPTAB ): c.3503_3504del, and a heterozygous missense variant, NM_024312.5( GNPTAB ): c.1400A>G, p.(Asp467Gly), occurring in trans . Enzymatic testing showed elevated plasma lysosomal enzyme activity, confirming the clinical diagnosis. Cardiomyopathy has rarely been reported in patients with ML III. Conclusion: We expand the cardiac phenotypic features of ML III and suggest that GNPTAB could be considered for testing in patients with genetically undiagnosed cardiomyopathy and/or sudden cardiac arrest. Medical Genetics Cardiac & Cardiovascular Systems GNPTAB Mucolipidosis Type III Pseudo-Hurler Polydystrophy Cardiomyopathy Sudden Cardiac Death Figures Figure 1 INTRODUCTION GNPTAB encodes the alpha and beta subunits of N-acetylglucosamine (GlcNAc)-1-phosphotransferase (GNPTA). This enzyme catalyzes the initial step of mannose-6-phosphate (M6P) tagging on lysosomal hydrolases, thereby allowing hydrolase transport to the lysosome via the M6P-dependent trafficking pathway. 1 Homozygous or compound heterozygous loss-of-function variants in GNPTAB cause mucolipidosis type II (ML II), a progressive multisystem disorder characterized by skeletal abnormalities, short stature, coarse facial features and cardiorespiratory disease. The condition is severe, typically presenting prenatally or in the neonatal period and leading to death within the first decade of life due to cardiorespiratory failure. 2 – 4 The pathogenesis of ML II arises from impaired transport of lysosomal enzymes, with aberrant secretion of lysosomal enzymes into the extracellular environment and accumulation of undigested molecules within lysosomes. 1 , 2 , 5 Mucolipidosis type III alpha/beta (ML III) is milder, with an older age of onset and a less severe phenotype. Patients carry one loss-of-function and one hypomorphic allele. 1 , 4 ML III has a variable presentation, likely due to the degree of residual enzymatic activity. 2 Common features include carpal tunnel syndrome, joint stiffness, gait disturbance and joint pain. Cardiorespiratory disease is absent or less pronounced relative to ML II. 2 CASE REPORT We report two siblings with compound heterozygous variants in GNPTAB. The male proband presented at ~ 10 years with gait disturbance and learning difficulties. Radiographs showed smooth thoracic kyphosis with mild anterior wedging of vertebral bodies, marked bilateral dysplasia of the femoral heads, and small distal and proximal tibial epiphyses. Several skeletal features were indicative of dysplastic processes, and bone changes resembled a mixed osteochondritis, including Scheuermann kyphosis and bilateral Perthes’ disease. Karyotyping was performed, and no abnormalities were identified. By his mid-20’s, he had reduced range of motion in the hips bilaterally with pain at the end points of flexion, internal and external rotation, and back deformity suggestive of scoliosis. His adult height was 1.72 m. The proband’s sister developed a gait disturbance as a teenager following a sprained ankle. By her 20’s, she had reduced range of motion in the hips bilaterally on flexion, internal and external rotation, a slightly asymmetric back suggestive of scoliosis, and joint stiffness after long walks. Her adult height was 1.57 m, and she reported having completed postgraduate University studies. The proband died suddenly in his early 30’s from a presumed ventricular arrhythmia. At postmortem there was an enlarged heart with morphologically abnormal left ventricular myocardium and fat infiltration of the right ventricle. Valves appeared normal. Microscopy of the heart identified dysmorphic myocytes with vacuolated cytoplasm and abnormal appearing nuclei, and there was extensive left ventricular fibrosis. The liver was enlarged and there was extensive steatosis without fibrosis or inflammation. His sister presented with cardiac symptoms in her late 20’s. She received an implantable loop recorder which revealed multiple episodes of polymorphic ventricular tachycardia. Echocardiogram and cardiac magnetic resonance imaging (CMR) showed dilation of her right ventricle (RVEDV 131 ml/m 2 ), prominent trabeculations, increased septal wall thickness (13 mm), reduced free wall systolic function, and mild-to-moderate systolic dysfunction (RV EF 37%, LV EF 57%). Significant diffuse non-ischemic global scarring of the left ventricle was identified on CMR with late gadolinium enhancement. She received an implantable cardioverter defibrillator, and during hospitalization, she experienced a ventricular tachycardia storm, with multiple events successfully terminated by anti-tachycardia pacing. Her VT stabilized post-discharge. The proband's sister underwent inconclusive clinical genetic testing of 218 cardiac disease-associated genes in 2022. The family were subsequently enrolled in Elusive Hearts, an Australian gene discovery study focused on identifying novel causes of heritable cardiovascular diseases. Following whole genome sequencing, we detected a heterozygous frameshift variant, NM_024312.5( GNPTAB ):c.3503_3504del, and a heterozygous missense variant, NM_024312.5( GNPTAB ):c.1400A > G, p.(Asp467Gly), in both siblings. We used Oxford Nanopore PromethION sequencing to confirm that both variants were in trans in the proband’s sister. The c.3503_3504del variant is the most common pathogenic GNPTAB variant and has been reported in patients with ML II in a homozygous state. 2 The p.(Asp467Gly) variant has not been reported in association with mucolipidosis. It is rare, with an allele frequency of 4.96 x 10 − 6 (gnomAD v4.1) and is predicted to be detrimental to protein function (REVEL 0.925, CADD 32.0, AlphaMissense 0.989). Residue Asp467 is situated within a notch repeat domain and is a predicted Ca 2+ binding site. Given that patients with ML III carry one hypomorphic and one loss-of-function allele, we suggest that this variant results in hypomorphic function, perhaps because the Asp-Gly substitution impairs Ca2 + binding. We did not identify any other variants that we considered explanatory for the siblings’ phenotype. The proband’s sister was evaluated by clinical services; the variants were confirmed with PCR and Sanger sequencing, and enzymatic testing revealed elevated plasma lysosomal enzyme activity, confirming a diagnosis of ML III. INSIGHTS While mitral/aortic valve thickening is commonly reported in ML III, 4 cardiomyopathy is a rare complication. 3 , 5 Our findings expand the phenotypic spectrum of ML III to include an adult-onset arrhythmic cardiomyopathy phenotype, in this example as the primary disease presentation. Based on these findings, GNPTAB could be considered for testing in patients with genetically undiagnosed cardiomyopathy and/or sudden cardiac arrest. Declarations A statement on participant consent to publish: The participants provided written and verbal consent for their de-identifiable information to be included in this publication. COMPETING INTERESTS JI is a consultant for Kardigan. DGM is an advisor to Insitro and GlaxoSmithKline, and has received research funding from Google, Microsoft, and the industry consortia Open Targets and Genes & Health. LY receives speaker fees from Bristol Myers Squibb. All other authors report no conflicts of interest. DATA AVAILABILITY All data produced in the present study are available upon reasonable request to the authors and following appropriate ethics and legal approval. References Braulke T, Carette JE, Palm W (2024) Lysosomal enzyme trafficking: from molecular mechanisms to human diseases. Trends Cell Biol 34(3):198–210 Velho RV, Harms FL, Danyukova T et al (2019) The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutations. Hum Mutat 40(7):842–864 Kwak MJ, Lee HW, Kim YM, Cho SY, Park HD, Jin DK (2018) Rare Association of Mucolipidosis III alpha/beta with Dilated Cardiomyopathy. Ann Clin Lab Sci 48(6):785–789 Cathey SS, Leroy JG, Wood T et al (2010) Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet 47(1):38–48 Kobayashi H, Takahashi-Fujigasaki J, Fukuda T et al (2011) Pathology of the first autopsy case diagnosed as mucolipidosis type III α/β suggesting autophagic dysfunction. Mol Genet Metab 102(2):170–175 Additional Declarations The authors declare potential competing interests as follows: JI is a consultant for Kardigan. DGM is an advisor to Insitro and GlaxoSmithKline, and has received research funding from Google, Microsoft, and the industry consortia Open Targets and Genes & Health. LY receives speaker fees from Bristol Myers Squibb. All other authors report no conflicts of interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8674450","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":579081806,"identity":"137de51f-9fc0-4164-bbcc-f6b4dab06fbd","order_by":0,"name":"Natalie Stewart","email":"","orcid":"","institution":"Garvan Institute of Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Natalie","middleName":"","lastName":"Stewart","suffix":""},{"id":579081807,"identity":"37795f28-c4a1-4e07-bcbf-36d4c1c7f82c","order_by":1,"name":"Natasha Henden","email":"","orcid":"","institution":"Garvan Institute of Medical 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The proband [II:1] died at the age of 31 from a presumed cardiac arrhythmia. \u003cstrong\u003eB:\u003c/strong\u003e Location of the Arg467 residue within the α-subunit (amino acids 1-928, teal) of \u003cem\u003eGNPTAB\u003c/em\u003eusing the AlphaFold structure AF-Q3T906-F1-model_v6. \u003cstrong\u003eC:\u003c/strong\u003e Variant phasing using Oxford Nanopore PromethION long read sequencing showing the c.1400A\u0026gt;G variant on allele 1 (blue) and the c.3503_3504del variant on allele 2 (red). \u003cstrong\u003eD-G\u003c/strong\u003e: Photomicrographs from the proband’s autopsy. \u003cstrong\u003eD:\u003c/strong\u003e Subendocardial third of the interventricular septum (H\u0026amp;E stain, 20x objective) showing loose and dense fibrous tissue both replacing and encircling dysmorphic appearing myocytes, and a limited chronic inflammatory cell infiltrate within areas of fibrosis. Many myocyte nuclei appear markedly dysmorphic. \u003cstrong\u003eE:\u003c/strong\u003eRepresentative section of the right ventricular outflow tract (Masson’s trichrome stain, 40x objective) showing extensive transmural fat infiltration, limited dysmorphic appearing myocytes (red) surrounded by fibrous tissue (blue). \u003cstrong\u003eF: \u003c/strong\u003eSubendocardial third of the interventricular septum (Masson’s trichrome stain, 10x objective) showing a combination of fibrosis (blue) and fat cells, with interspersed dysmorphic appearing myocytes (red). There is scanty chronic inflammation within the areas of fibrosis. \u003cstrong\u003eG: \u003c/strong\u003eRepresentative section of the liver (H\u0026amp;E stain, 10x objective), showing near-confluent micro/macrovesicular steatosis without excess fibrosis or an inflammatory infiltrate.\u003cstrong\u003e H-J:\u003c/strong\u003e Cardiac magnetic resonance imaging from the proband’s sister. \u003cstrong\u003eH: \u003c/strong\u003eStill frame from a four-chamber cine sequence showing right ventricular dilatation and septal hypertrophy. \u003cstrong\u003eI:\u003c/strong\u003e Four-chamber late gadolinium enhancement imaging showing diffuse left ventricular uptake \u003cstrong\u003eJ:\u003c/strong\u003eShort-axis late gadolinium enhancement images showing diffuse left ventricular uptake and prominent trabeculations (white arrow).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8674450/v1/c0ffa027e61aeee20b6fc0d0.png"},{"id":101362786,"identity":"6bbc8e94-1016-4ae4-8751-843dbd5c2708","added_by":"auto","created_at":"2026-01-29 00:32:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4400031,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8674450/v1/99a15e99-e52c-4b42-88e8-a198b08f7a7e.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: JI is a consultant for Kardigan. DGM is an advisor to Insitro and GlaxoSmithKline, and has received research funding from Google, Microsoft, and the industry consortia Open Targets and Genes \u0026 Health. LY receives speaker fees from Bristol Myers Squibb. All other authors report no conflicts of interest.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCardiomyopathy and sudden cardiac death as a rare presentation of mucolipidosis type III in a family with compound heterozygous variants in \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eGNPTAB\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003e \u003cem\u003eGNPTAB\u003c/em\u003e encodes the alpha and beta subunits of N-acetylglucosamine (GlcNAc)-1-phosphotransferase (GNPTA). This enzyme catalyzes the initial step of mannose-6-phosphate (M6P) tagging on lysosomal hydrolases, thereby allowing hydrolase transport to the lysosome via the M6P-dependent trafficking pathway.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Homozygous or compound heterozygous loss-of-function variants in \u003cem\u003eGNPTAB\u003c/em\u003e cause mucolipidosis type II (ML II), a progressive multisystem disorder characterized by skeletal abnormalities, short stature, coarse facial features and cardiorespiratory disease. The condition is severe, typically presenting prenatally or in the neonatal period and leading to death within the first decade of life due to cardiorespiratory failure.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The pathogenesis of ML II arises from impaired transport of lysosomal enzymes, with aberrant secretion of lysosomal enzymes into the extracellular environment and accumulation of undigested molecules within lysosomes.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMucolipidosis type III alpha/beta (ML III) is milder, with an older age of onset and a less severe phenotype. Patients carry one loss-of-function and one hypomorphic allele.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e ML III has a variable presentation, likely due to the degree of residual enzymatic activity.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Common features include carpal tunnel syndrome, joint stiffness, gait disturbance and joint pain. Cardiorespiratory disease is absent or less pronounced relative to ML II.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e"},{"header":"CASE REPORT","content":"\u003cp\u003eWe report two siblings with compound heterozygous variants in \u003cem\u003eGNPTAB.\u003c/em\u003e The male proband presented at ~\u0026thinsp;10 years with gait disturbance and learning difficulties. Radiographs showed smooth thoracic kyphosis with mild anterior wedging of vertebral bodies, marked bilateral dysplasia of the femoral heads, and small distal and proximal tibial epiphyses. Several skeletal features were indicative of dysplastic processes, and bone changes resembled a mixed osteochondritis, including Scheuermann kyphosis and bilateral Perthes\u0026rsquo; disease. Karyotyping was performed, and no abnormalities were identified. By his mid-20\u0026rsquo;s, he had reduced range of motion in the hips bilaterally with pain at the end points of flexion, internal and external rotation, and back deformity suggestive of scoliosis. His adult height was 1.72 m. The proband\u0026rsquo;s sister developed a gait disturbance as a teenager following a sprained ankle. By her 20\u0026rsquo;s, she had reduced range of motion in the hips bilaterally on flexion, internal and external rotation, a slightly asymmetric back suggestive of scoliosis, and joint stiffness after long walks. Her adult height was 1.57 m, and she reported having completed postgraduate University studies.\u003c/p\u003e \u003cp\u003eThe proband died suddenly in his early 30\u0026rsquo;s from a presumed ventricular arrhythmia. At postmortem there was an enlarged heart with morphologically abnormal left ventricular myocardium and fat infiltration of the right ventricle. Valves appeared normal. Microscopy of the heart identified dysmorphic myocytes with vacuolated cytoplasm and abnormal appearing nuclei, and there was extensive left ventricular fibrosis. The liver was enlarged and there was extensive steatosis without fibrosis or inflammation. His sister presented with cardiac symptoms in her late 20\u0026rsquo;s. She received an implantable loop recorder which revealed multiple episodes of polymorphic ventricular tachycardia. Echocardiogram and cardiac magnetic resonance imaging (CMR) showed dilation of her right ventricle (RVEDV 131 ml/m\u003csup\u003e2\u003c/sup\u003e), prominent trabeculations, increased septal wall thickness (13 mm), reduced free wall systolic function, and mild-to-moderate systolic dysfunction (RV EF 37%, LV EF 57%). Significant diffuse non-ischemic global scarring of the left ventricle was identified on CMR with late gadolinium enhancement. She received an implantable cardioverter defibrillator, and during hospitalization, she experienced a ventricular tachycardia storm, with multiple events successfully terminated by anti-tachycardia pacing. Her VT stabilized post-discharge.\u003c/p\u003e \u003cp\u003eThe proband's sister underwent inconclusive clinical genetic testing of 218 cardiac disease-associated genes in 2022. The family were subsequently enrolled in Elusive Hearts, an Australian gene discovery study focused on identifying novel causes of heritable cardiovascular diseases. Following whole genome sequencing, we detected a heterozygous frameshift variant, NM_024312.5(\u003cem\u003eGNPTAB\u003c/em\u003e):c.3503_3504del, and a heterozygous missense variant, NM_024312.5(\u003cem\u003eGNPTAB\u003c/em\u003e):c.1400A\u0026thinsp;\u0026gt;\u0026thinsp;G, p.(Asp467Gly), in both siblings. We used Oxford Nanopore PromethION sequencing to confirm that both variants were in \u003cem\u003etrans\u003c/em\u003e in the proband\u0026rsquo;s sister.\u003c/p\u003e \u003cp\u003eThe c.3503_3504del variant is the most common pathogenic \u003cem\u003eGNPTAB\u003c/em\u003e variant and has been reported in patients with ML II in a homozygous state.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The p.(Asp467Gly) variant has not been reported in association with mucolipidosis. It is rare, with an allele frequency of 4.96 x 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e (gnomAD v4.1) and is predicted to be detrimental to protein function (REVEL 0.925, CADD 32.0, AlphaMissense 0.989). Residue Asp467 is situated within a notch repeat domain and is a predicted Ca\u003csup\u003e2+\u003c/sup\u003e binding site. Given that patients with ML III carry one hypomorphic and one loss-of-function allele, we suggest that this variant results in hypomorphic function, perhaps because the Asp-Gly substitution impairs Ca2\u0026thinsp;+\u0026thinsp;binding. We did not identify any other variants that we considered explanatory for the siblings\u0026rsquo; phenotype. The proband\u0026rsquo;s sister was evaluated by clinical services; the variants were confirmed with PCR and Sanger sequencing, and enzymatic testing revealed elevated plasma lysosomal enzyme activity, confirming a diagnosis of ML III.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eINSIGHTS\u003c/h2\u003e \u003cp\u003eWhile mitral/aortic valve thickening is commonly reported in ML III,\u003csup\u003e4\u003c/sup\u003e cardiomyopathy is a rare complication.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Our findings expand the phenotypic spectrum of ML III to include an adult-onset arrhythmic cardiomyopathy phenotype, in this example as the primary disease presentation. Based on these findings, \u003cem\u003eGNPTAB\u003c/em\u003e could be considered for testing in patients with genetically undiagnosed cardiomyopathy and/or sudden cardiac arrest.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eA statement on participant consent to publish: The participants provided written and verbal consent for their de-identifiable information to be included in this publication.\u003c/p\u003e\u003cp\u003e \u003ch2\u003eCOMPETING INTERESTS\u003c/h2\u003e \u003cp\u003eJI is a consultant for Kardigan. DGM is an advisor to Insitro and GlaxoSmithKline, and has received research funding from Google, Microsoft, and the industry consortia Open Targets and Genes \u0026amp; Health. LY receives speaker fees from Bristol Myers Squibb. All other authors report no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eDATA AVAILABILITY\u003c/h2\u003e \u003cp\u003eAll data produced in the present study are available upon reasonable request to the authors and following appropriate ethics and legal approval.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBraulke T, Carette JE, Palm W (2024) Lysosomal enzyme trafficking: from molecular mechanisms to human diseases. Trends Cell Biol 34(3):198\u0026ndash;210\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVelho RV, Harms FL, Danyukova T et al (2019) The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutations. Hum Mutat 40(7):842\u0026ndash;864\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwak MJ, Lee HW, Kim YM, Cho SY, Park HD, Jin DK (2018) Rare Association of Mucolipidosis III alpha/beta with Dilated Cardiomyopathy. Ann Clin Lab Sci 48(6):785\u0026ndash;789\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCathey SS, Leroy JG, Wood T et al (2010) Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet 47(1):38\u0026ndash;48\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobayashi H, Takahashi-Fujigasaki J, Fukuda T et al (2011) Pathology of the first autopsy case diagnosed as mucolipidosis type III α/β suggesting autophagic dysfunction. Mol Genet Metab 102(2):170\u0026ndash;175\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"GNPTAB, Mucolipidosis Type III, Pseudo-Hurler Polydystrophy, Cardiomyopathy, Sudden Cardiac Death","lastPublishedDoi":"10.21203/rs.3.rs-8674450/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8674450/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eHomozygous or compound heterozygous loss-of-function variants in \u003cem\u003eGNPTAB \u003c/em\u003ecause mucolipidosis type II/III, a progressive multisystem disorder characterized by skeletal abnormalities, short stature, coarse facial features and cardiorespiratory disease. ML III is milder, with an older age of onset and a less severe phenotype. We report two siblings with arrhythmogenic cardiomyopathy and ventricular arrhythmias with compound heterozygous variants in \u003cem\u003eGNPTAB.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and Results: \u003c/strong\u003eThe family presented due to the sudden cardiac death of a male in his early 30’s with arrhythmogenic cardiomyopathy identified at autopsy. His sister was found to have cardiomyopathy and experienced a ventricular tachycardia storm. Both siblings had history of skeletal dysplasia first investigated during adolescence. Clinical genetic testing did not identify a cause for the cardiomyopathy, and they were enrolled in the Elusive Hearts study. Following whole genome sequencing, we detected a heterozygous frameshift variant, NM_024312.5(\u003cem\u003eGNPTAB\u003c/em\u003e): c.3503_3504del, and a heterozygous missense variant, NM_024312.5(\u003cem\u003eGNPTAB\u003c/em\u003e): c.1400A\u0026gt;G, p.(Asp467Gly), occurring \u003cem\u003ein trans\u003c/em\u003e. Enzymatic testing showed elevated plasma lysosomal enzyme activity, confirming the clinical diagnosis. Cardiomyopathy has rarely been reported in patients with ML III.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eWe expand the cardiac phenotypic features of ML III and suggest\u003cem\u003e \u003c/em\u003ethat \u003cem\u003eGNPTAB\u003c/em\u003ecould be considered for testing in patients with genetically undiagnosed cardiomyopathy and/or sudden cardiac arrest.\u003c/p\u003e","manuscriptTitle":"Cardiomyopathy and sudden cardiac death as a rare presentation of mucolipidosis type III in a family with compound heterozygous variants in GNPTAB","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 00:32:01","doi":"10.21203/rs.3.rs-8674450/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f967c68-4c0c-499a-b3f7-6ce70c73ed73","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61614042,"name":"Medical Genetics"},{"id":61614043,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2026-01-29T00:32:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 00:32:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8674450","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8674450","identity":"rs-8674450","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}