{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:25:21Z","timestamp":1771028721266,"version":"3.50.1"},"reference-count":20,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Distal arthrogryposis type 5D (DA5D), a rare autosomal recessive disorder, is caused by mutations in ECEL1. We describe two consanguineous families (three patients) with novel ECEL1 gene mutations detected by next-generation sequencing (NGS). A 12-year-old boy (patient 1) presented with birth asphyxia, motor developmental delay, multiple joint contractures, pes planus, kyphoscoliosis, undescended testis, hypophonic speech with a nasal twang, asymmetric ptosis, facial weakness, absent abductor pollicis brevis, bifacial, and distal lower limb weakness. Muscle MRI revealed asymmetric fatty infiltration of tensor fascia lata, hamstring, lateral compartment of the leg, and gastrocnemius. In addition, 17-year-old monozygotic twins (patients 2 and 3) presented with motor development delay, white hairlock, hypertelorism, tented upper lip, bulbous nose, tongue furrowing, small low set ears, multiple contractures, pes cavus, prominent hyperextensibility at the knee, hypotonia of lower limbs, wasting and weakness of all limbs (distal &gt; proximal), areflexia, and high steppage gait. One had perinatal insult, seizures, mild intellectual disability, unconjugated eye movements, and primary optic atrophy. In the twins, MRI revealed extensive fatty infiltration of the gluteus maximus, quadriceps, hamstrings, and anterior and posterior compartment of the leg. Electrophysiology showed prominent motor axonopathy. NGS revealed rare homozygous missense variants c.602T &gt; C (p.Met201Thr) in patient 1 and c.83C &gt; T (p.Ala28Val) in patients 2 and 3, both localized in exon 2 of ECEL1 gene. Our three cases expand the clinical, imaging, and molecular spectrum of the ECEL1-mutation-related DA5D.<\/jats:p>","DOI":"10.3390\/children8100909","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:36:15Z","timestamp":1634160975000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Expanding the Phenotypic Spectrum of ECEL1-Associated Distal Arthrogryposis"],"prefix":"10.3390","volume":"8","author":[{"given":"Akshata","family":"Huddar","sequence":"first","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiran","family":"Polavarapu","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Department of Medicine, Division of Neurology, The Ottawa Hospital, Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1158-0971","authenticated-orcid":false,"given":"Veeramani","family":"Preethish-Kumar","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4106-409X","authenticated-orcid":false,"given":"Mainak","family":"Bardhan","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gopikrishnan","family":"Unnikrishnan","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saraswati","family":"Nashi","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seena","family":"Vengalil","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyanka","family":"Priyadarshini","sequence":"additional","affiliation":[{"name":"Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1585-8769","authenticated-orcid":false,"given":"Karthik","family":"Kulanthaivelu","sequence":"additional","affiliation":[{"name":"Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9985-7028","authenticated-orcid":false,"given":"Gautham","family":"Arunachal","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute, Department of Medicine, Division of Neurology, The Ottawa Hospital, Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atchayaram","family":"Nalini","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Institute of Mental Health and Neuro-Sciences, Bengaluru 560029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ejmg.2014.03.008","article-title":"Arthrogryposis (multiple congenital contractures): Diagnostic approach to etiology, classification, genetics, and general principles","volume":"57","author":"Hall","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/(SICI)1096-8628(19961111)65:4<277::AID-AJMG6>3.0.CO;2-M","article-title":"A revised and extended classification of the distal arthrogryposes","volume":"65","author":"Bamshad","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.ajhg.2012.11.014","article-title":"Mutations in ECEL1 cause distal arthrogryposis type 5D","volume":"92","author":"McMillin","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/hmg\/dds514","article-title":"The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis","volume":"22","author":"Dieterich","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fped.2019.00343","article-title":"Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D)","volume":"7","author":"Umair","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human Splicing Finder: An online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2149342","DOI":"10.1155\/2020\/2149342","article-title":"The Novel Compound Heterozygous Mutations of ECEL1 Identified in a Family with Distal Arthrogryposis Type 5D","volume":"2020","author":"Jin","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.nmd.2018.05.012","article-title":"ECEL1 gene related contractural syndrome: Long-term follow-up and update on clinical and pathological aspects","volume":"28","author":"Ullmann","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1111\/cge.12226","article-title":"Identification of three novel ECEL1 mutations in three families with distal arthrogryposis type 5D","volume":"85","author":"Shaheen","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/cge.12224","article-title":"Expanding the phenotypic spectrum of ECEL1-related congenital contracture syndromes","volume":"85","author":"Shaaban","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1002\/ajmg.a.36702","article-title":"Distal arthrogryposis type 5D with a novel ECEL1 gene mutation","volume":"164A","author":"Patil","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1002\/ajmg.a.36342","article-title":"Distal arthrogryposis type 5D with novel clinical features and compound heterozygous mutations in ECEL1","volume":"164A","author":"Barnett","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1172\/JCI84457","article-title":"Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin","volume":"126","author":"Bayram","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000456034","article-title":"A Novel Variant in the Endothelin-Converting Enzyme-Like 1 (ECEL1) Gene in an Emirati Child","volume":"26","author":"Hamzeh","year":"2017","journal-title":"Med. Princ. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/ajmg.a.38691","article-title":"A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases","volume":"176","author":"Stattin","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Alesi, V., Sessini, F., Genovese, S., Calvieri, G., Sallicandro, E., Ciocca, L., Mingoia, M., Novelli, A., and Moi, P. (2021). A New Intronic Variant in ECEL1 in Two Patients with Distal Arthrogryposis Type 5D. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22042106"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1093\/hmg\/ddt618","article-title":"Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects","volume":"23","author":"Maluenda","year":"2014","journal-title":"Hum. Mol. Genet."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/8\/10\/909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:12:32Z","timestamp":1760166752000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/8\/10\/909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,13]]},"references-count":20,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["children8100909"],"URL":"https:\/\/doi.org\/10.3390\/children8100909","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,13]]}}}