{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T22:56:05Z","timestamp":1782773765542,"version":"3.54.5"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>TCIRG1 gene mutations underlie osteopetrosis, a rare genetic disorder impacting osteoclast function with consequent brittle bones prone to fracture, in spite of being characterized by increased bone density. The disorder is known to exhibit marked genetic heterogeneity, has no treatment, and is lethal in most instances. There are reports of ethnic variations affecting bone mineral density and variants\u2019 expression as diverse phenotypes even within individuals descending from the same pedigree. We herein focus on one of osteopetrosis\u2019s three types: the autosomal recessive malignant form (MIM 259700) (ARO) that is almost always associated with severe clinical symptoms. We reviewed the results of about 1800 Egyptian exomes and we did not detect similar variants within our Egyptian dataset and secondary neurological deficit. We studied twenty Egyptian families: sixteen ARO patients, ten carrier parents with at least one ARO affected sib, and two fetuses. They were all subjected to thorough evaluation and TCIRG1 gene sequencing. Our results of twenty-eight individuals descending from twenty Egyptian pedigrees with at least one ARO patient, expand the phenotype as well as genotype spectrum of recessive mutations in the TCIRG1 gene by five novel pathogenic variants. Identifying TCIRG1 gene mutations in Egyptian patients with ARO allowed the provision of proper genetic counseling, carrier detection, and prenatal diagnosis starting with two families included herein. It also could pave the way to modern genomic therapeutic approaches.<\/jats:p>","DOI":"10.3390\/genes14040900","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T02:29:15Z","timestamp":1681352955000},"page":"900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-1674","authenticated-orcid":false,"given":"Ghada Y.","family":"El-Kamah","sequence":"first","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-4024","authenticated-orcid":false,"given":"Mennat I.","family":"Mehrez","sequence":"additional","affiliation":[{"name":"Oro-Dental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed B.","family":"Taher","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9825-1219","authenticated-orcid":false,"given":"Hala T.","family":"El-Bassyouni","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled R.","family":"Gaber","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis and Fetal Medicine Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalda S.","family":"Amr","sequence":"additional","affiliation":[{"name":"Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"ref_1","first-page":"e21886","article-title":"Managing Osteopetrosis in the Complex Polytrauma Orthopedic Patient","volume":"14","author":"Sabacinski","year":"2022","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11914-018-0415-2","article-title":"Genetics of Osteopetrosis","volume":"16","author":"Palagano","year":"2018","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fendo.2015.00024","article-title":"Ethnic differences in bone health","volume":"6","author":"Zengin","year":"2015","journal-title":"Front. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"920390","DOI":"10.3389\/fgene.2022.920390","article-title":"Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts","volume":"13","author":"Kingdom","year":"2022","journal-title":"Front. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3324\/haematol.2019.238261","article-title":"Expanded circulating hematopoietic stem\/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis","volume":"106","author":"Capo","year":"2021","journal-title":"Haematologica"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12887-021-02774-1","article-title":"Two novel mutations in TCIRG1 induced infantile malignant osteopetrosis: A case report","volume":"21","author":"Wu","year":"2021","journal-title":"BMC Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1210\/jc.2017-01127","article-title":"Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group","volume":"102","author":"Wu","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bone.2017.02.002","article-title":"Osteopetroses, emphasizing potential approaches to treatment","volume":"102","author":"Teti","year":"2017","journal-title":"Bone"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.32723","article-title":"TANGO1 builds a machine for collagen export by recruiting and spatially organizing COPII, tethers and membranes","volume":"7","author":"Raote","year":"2018","journal-title":"Elife"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e224452","DOI":"10.1136\/bcr-2018-224452","article-title":"Osteomyelitis of the mandible secondary to malignant infantile osteopetrosis in an adult","volume":"12","author":"Dunphy","year":"2019","journal-title":"BMJ Case Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/pbc.25801","article-title":"Improved Outcomes of Hematopoietic Stem Cell Transplantation in Patients with Infantile Malignant Osteopetrosis Using Fludarabine-Based Conditioning","volume":"63","author":"Natsheh","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/scd.12427","article-title":"When a pedodontic examination leads to the diagnosis of osteopetrosis: A case report","volume":"40","author":"Athanasiadou","year":"2020","journal-title":"Spec. Care Dent."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrendo.2013.137","article-title":"Osteopetrosis: Genetics, treatment and new insights into osteoclast function","volume":"9","author":"Sobacchi","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/77131","article-title":"Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis","volume":"25","author":"Frattini","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1093\/hmg\/9.13.2059","article-title":"Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis","volume":"9","author":"Kornak","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6701","DOI":"10.1038\/s41598-018-24918-7","article-title":"Essential Role of the a3 Isoform of V-ATPase in Secretory Lysosome Trafficking via Rab7 Recruitment","volume":"8","author":"Matsumoto","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1073\/pnas.80.9.2752","article-title":"Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification","volume":"80","author":"Sly","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1093\/hmg\/10.25.2861","article-title":"Albers-Sch\u00f6nberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene","volume":"10","author":"Cleiren","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0092-8674(01)00206-9","article-title":"Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man","volume":"104","author":"Kornak","year":"2001","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1359\/jbmr.2003.18.10.1740","article-title":"Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis","volume":"18","author":"Frattini","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nm842","article-title":"Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human","volume":"9","author":"Chalhoub","year":"2003","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chen, Y., Lu, H., Zhang, N., Zhu, Z., Wang, S., and Li, M. (2020). PremPS: Predicting the impact of missense mutations on protein stability. PLoS Comput. Biol., 16.","DOI":"10.1371\/journal.pcbi.1008543"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1093\/hmg\/10.17.1767","article-title":"The mutational spectrum of human malignant autosomal recessive osteopetrosis","volume":"10","author":"Sobacchi","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/ajh.21447","article-title":"A single-center experience in 20 patients with infantile malignant osteopetrosis","volume":"84","author":"Mazzolari","year":"2009","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/cge.12460","article-title":"Predictive genetic testing for adult-onset disorders in minors: A critical analysis of the arguments for and against the 2013 ACMG guidelines","volume":"87","author":"Anderson","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1002\/jbmr.2517","article-title":"Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis","volume":"30","author":"Palagano","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e539","DOI":"10.1097\/HS9.0000000000000539","article-title":"Next-generation Sequencing in Bone Marrow Failure Syndromes and Isolated Cytopenias: Experience of the Spanish Network on Bone Marrow Failure Syndromes","volume":"5","author":"Navarro","year":"2021","journal-title":"Hemasphere"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108","DOI":"10.29262\/ram.v65i1.314","article-title":"Identificaci\u00f3n de nuevas mutaciones en TCIRG1 como causa de osteopetrosis maligna infantil en dos pacientes mexicanos [Identification of new mutations in TCIRG1 as a cause of infantile malignant osteopetrosis in two Mexican patients]","volume":"65","author":"Sobacchi","year":"2018","journal-title":"Rev. Alerg. Mex."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1007\/s00198-011-1878-5","article-title":"Autosomal recessive osteopetrosis: Report of 41 novel mutations in the TCIRG1 gene and diagnostic implications","volume":"23","author":"Pangrazio","year":"2012","journal-title":"Osteoporos. Int."},{"key":"ref_31","first-page":"377","article-title":"Analysis of TCIRG1 gene mutation in a Chinese family affected with infantile malignant osteopetrosis","volume":"34","author":"Wang","year":"2017","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"ref_32","first-page":"578","article-title":"Some genetic and surgical aspects of the cleft lip-cleft palate problem in Egypt","volume":"7","author":"Temtamy","year":"1970","journal-title":"Cleft Palate J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1515\/JPEM.2001.14.9.1671","article-title":"Osteopetrosis, renal tubular acidosis without urinary concentration abnormality, cerebral calcification and severe mental retardation in three Turkish brothers","volume":"14","author":"Ocal","year":"2001","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_34","first-page":"SJ01","article-title":"A Rare Case of Osteopetrosis with Unusual Feature as Microcephaly","volume":"11","author":"Bhati","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_35","first-page":"123","article-title":"Three sibs with mild variety of osteopetrosis","volume":"42","author":"Shah","year":"1996","journal-title":"J. Postgrad. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, J., Liu, Y., Kim, T.H., Min, R., and Zhang, Z. (2010). Gene expression variability within and between human populations and implications toward disease susceptibility. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1000910"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bone.2012.11.009","article-title":"Osteopetrosis, osteopetrorickets and hypophosphatemic rickets differentially affect dentin and enamel mineralization","volume":"53","author":"Koehne","year":"2013","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/nrm729","article-title":"The vacuolar (H+)-ATPases--nature\u2019s most versatile proton pumps","volume":"3","author":"Nishi","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/humu.20076","article-title":"TCIRG1-dependent recessive osteopetrosis: Mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA","volume":"24","author":"Susani","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e000180","DOI":"10.1136\/bmjophth-2018-000180","article-title":"Ophthalmic phenotype of TCIRG1 gene mutations in Chinese infantile malignant osteopetrosis","volume":"3","author":"Cao","year":"2018","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/humu.22563","article-title":"TCIRG1-associated congenital neutropenia","volume":"35","author":"Makaryan","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1002\/jcb.24630","article-title":"The R740S mutation in the V-ATPase a3 subunit results in osteoclast apoptosis and defective early-stage autophagy","volume":"114","author":"Ochotny","year":"2013","journal-title":"J. Cell. Biochem."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/4\/900\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:14:52Z","timestamp":1760123692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/4\/900"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,12]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["genes14040900"],"URL":"https:\/\/doi.org\/10.3390\/genes14040900","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,12]]}}}