{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:11:25Z","timestamp":1792185085121,"version":"4.4.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Osteopetrosis is a genetically heterogenous, fatal bone disorder characterized by increased bone density. Globally, various genetic causes are reported for osteopetrosis with all forms of inheritance patterns. A precise molecular diagnosis is necessary for prognosis and for prescribing treatment paradigms in osteopetrosis. Here we report on thirteen individuals diagnosed with infantile malignant osteopetrosis coming from ten unrelated Pakistani families; nine of whom are consanguineous. We performed whole exome sequencing and Sanger sequencing in all families and identified homozygous variants in genes previously reported for autosomal recessive inheritance of osteopetrosis. All the identified variants are expected to affect the stability or length of gene products except one nonsynonymous missense variant. <jats:italic>TCIRG1<\/jats:italic> was found as a candidate causal gene in majority of the families. We report six novel variants; four in <jats:italic>TCIRG1<\/jats:italic> and one each in <jats:italic>CLCN7<\/jats:italic> and <jats:italic>OSTM1<\/jats:italic>. Our combined findings will be helpful in molecular diagnosis and genetic counselling of patients with osteopetrosis particularly in populations with high consanguinity.<\/jats:p>","DOI":"10.1186\/s12920-021-01117-4","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T11:02:39Z","timestamp":1636455759000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic analysis of osteopetrosis in Pakistani families identifies novel and known sequence variants"],"prefix":"10.1186","volume":"14","author":[{"given":"Chunyu","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Ajmal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaineb","family":"Akram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq","family":"Ghafoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Farhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sobia","family":"Shafique","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sughra","family":"Wahid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahar","family":"Bano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiu","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humayoon Shafique","family":"Satti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahir Naeem","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"1117_CR1","doi-asserted-by":"publisher","first-page":"3111","DOI":"10.1210\/jc.2017-01127","volume":"102","author":"CC Wu","year":"2017","unstructured":"Wu CC, Econs MJ, DiMeglio LA, Insogna KL, Levine MA, Orchard PJ, Miller WP, Petryk A, Rush ET, Shoback DM, et al. Diagnosis and management of osteopetrosis: consensus guidelines from the osteopetrosis working group. J Clin Endocrinol Metab. 2017;102:3111\u201323.","journal-title":"J Clin Endocrinol Metab"},{"key":"1117_CR2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3389\/fendo.2019.00085","volume":"10","author":"S Penna","year":"2019","unstructured":"Penna S, Capo V, Palagano E, Sobacchi C, Villa A. One disease, many genes: implications for the treatment of osteopetroses. Front Endocrinol. 2019;10:85.","journal-title":"Front Endocrinol"},{"key":"1117_CR3","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/nrendo.2013.137","volume":"9","author":"C Sobacchi","year":"2013","unstructured":"Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013;9:522\u201336.","journal-title":"Nat Rev Endocrinol"},{"key":"1117_CR4","first-page":"255","volume":"75","author":"LE Chavez-Guitron","year":"2018","unstructured":"Chavez-Guitron LE, Ceron-Torres T, Sobacchi C, Ochoa-Ruiz E, Villegas-Huesca S. Autosomal recessive osteopetrosis type I: description of pathogenic variant of TCIRG1 gene. Boletin Med Hosp Infantil Mex. 2018;75:255\u20139.","journal-title":"Boletin Med Hosp Infantil Mex"},{"key":"1117_CR5","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1016\/j.ajhg.2019.03.010","volume":"104","author":"N Oosterhof","year":"2019","unstructured":"Oosterhof N, Chang IJ, Karimiani EG, Kuil LE, Jensen DM, Daza R, Young E, Astle L, van der Linde HC, Shivaram GM, et al. Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am J Hum Genet. 2019;104:936\u201347.","journal-title":"Am J Hum Genet"},{"key":"1117_CR6","unstructured":"Sobacchi C, Villa A, Schulz A, Kornak U. CLCN7-Related Osteopetrosis. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews((R)). Seattle; 1993."},{"key":"1117_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00223-008-9196-4","volume":"84","author":"A Villa","year":"2009","unstructured":"Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int. 2009;84:1\u201312.","journal-title":"Calcif Tissue Int"},{"key":"1117_CR8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s11914-018-0415-2","volume":"16","author":"E Palagano","year":"2018","unstructured":"Palagano E, Menale C, Sobacchi C, Villa A. Genetics of osteopetrosis. Curr Osteoporos Rep. 2018;16:13\u201325.","journal-title":"Curr Osteoporos Rep"},{"key":"1117_CR9","first-page":"405","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. 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. Genet Med Off J Am Coll Med Genet. 2015;17:405\u201324.","journal-title":"Genet Med Off J Am Coll Med Genet"},{"key":"1117_CR10","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1007\/s00198-011-1878-5","volume":"23","author":"A Pangrazio","year":"2012","unstructured":"Pangrazio A, Caldana ME, Lo Iacono N, Mantero S, Vezzoni P, Villa A, Sobacchi C. Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications. 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Mol Biol Rep. 2018;45:565\u201370.","journal-title":"Mol Biol Rep"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-021-01117-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-021-01117-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-021-01117-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T11:02:45Z","timestamp":1636455765000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-021-01117-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,9]]},"references-count":16,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1117"],"URL":"https:\/\/doi.org\/10.1186\/s12920-021-01117-4","relation":{},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,9]]},"assertion":[{"value":"8 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Legal guardians of the patients (parents) gave consent for participation in this study and for publication of data without disclosing their identity. Ethical aspects of the studies and procedures related to clinical examination, human sample collection and genetic analysis were approved by Institutional Reviews Boards and Ethical committees of participating institutes (see \u201c\u201d section); Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan (families OP1, OP2, OP3, OP4) and Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan. All methods were performed in accordance with the relevant guidelines and regulations of The Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written consent to publish study findings was obtained from legal guardians of the affected individuals. Probands in current study are children under 17\u00a0years of age therefore consent to publish was collected from the parents\/guardians. The purpose of the study and its importance to patients and scientific community was explained to the parents of the affected individuals in their local language by the clinicians. The guardians gave written consent without revealing their identity in publication. Clinicians involved in the disease diagnosis coordinated the consent to PI and research team for genetic investigations.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"264"}}