Details of Disease

General Information of Disease (ID: DIS8C3LZ)

• Disease Name: Infantile malignant osteopetrosis
• Synonyms: malignant osteopetrosis; osteopetrosis (disease), autosomal recessive; autosomal recessive malignant osteopetrosis; autosomal recessive osteopetrosis; infantile malignant osteopetrosis; OPTB; autosomal recessive osteopetrosis (disease)
• Disease Class: LD24: Skeletal anomaly
• Definition: An autosomal recessive form of osteopetrosis caused by mutation(s) in at least 8 genes related to osteoclast function. This condition is characterized by the failure of osteoclasts to resorb bone, resulting in impaired bone modeling/remodeling, and skeletal fragility despite increased bone mass; it is also associated with hematopoietic insufficiency, hypocalcemia, disturbed tooth eruption, nerve entrapment syndromes, and growth impairment. Some cases are also associated with progressive neurological deterioration.
• Disease Hierarchy:
  DISCPWH9: Autosomal recessive disease
  DIS4DFBG: Hereditary optic neuropathy
  DIS7GHNM: Osteopetrosis
  DIS8C3LZ: Infantile malignant osteopetrosis
• ICD Code: ICD-11: ICD-11: LD24.10
• Disease Identifiers:
  MONDO ID: MONDO_0019026
  UMLS CUI: C4272578
  MedGen ID: 1385510
  Orphanet ID: 667
  SNOMED CT ID: 367489004

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
RP-L401	DMR4CX3	Phase 1	Gene therapy	[1]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 9 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CLCN7	TTST1AJ	Disputed	Genetic Variation	[2]
TCIRG1	TTVRN05	Disputed	Genetic Variation	[3]
CLCN7	TTST1AJ	Supportive	Autosomal recessive	[4]
TNFSF11	TT9E8HR	Supportive	Autosomal recessive	[5]
CA2	TTANPDJ	Strong	Biomarker	[6]
TNFRSF11A	TT3K9S2	Strong	Genetic Variation	[7]
HCAR1	TTVK4ZO	Definitive	Biomarker	[8]
HCAR2	TTWNV8U	Definitive	Biomarker	[8]
TCIRG1	TTVRN05	Definitive	Autosomal recessive	[9]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC4A4	DTWDEIL	Definitive	Genetic Variation	[10]

This Disease Is Related to 12 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
OSTM1	OTKNJDH7	Disputed	Biomarker	[11]
CLCN7	OTJVSUK1	Supportive	Autosomal recessive	[4]
SNX10	OT05B7BT	Supportive	Autosomal recessive	[12]
TNFSF11	OTJEPKEQ	Supportive	Autosomal recessive	[5]
ADO	OTRLGQ7V	Strong	Biomarker	[13]
PLEKHM1	OT1SLPGD	Strong	Biomarker	[14]
ADCY10	OTYSTB0R	Definitive	Biomarker	[8]
ANXA7	OTLMD0TK	Definitive	Altered Expression	[15]
ATP6V1B1	OT8FQ7MN	Definitive	Genetic Variation	[10]
MAGEC3	OT0KDWZN	Definitive	Biomarker	[8]
MAGEE1	OTOQQO2X	Definitive	Biomarker	[8]
TCIRG1	OTU1AIEW	Definitive	Autosomal recessive	[9]

References

• [1] ClinicalTrials.gov (NCT04525352) A Phase I Clinical Trial for Gene Therapy in Infantile Malignant Osteopetrosis (IMO) to Evaluate the Safety and Preliminary Efficacy of Autologous CD34+ Enriched Cells Transduced With a LV Vector Encoding the TCIRG1 Gene. U.S.National Institutes of Health.
• [2] Generation of a human induced pluripotent stem cell line (BIHi002-A) from a patient with CLCN7-related infantile malignant autosomal recessive osteopetrosis.Stem Cell Res. 2019 Mar;35:101367. doi: 10.1016/j.scr.2018.101367. Epub 2018 Dec 26.
• [3] Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Autosomal Recessive Osteopetrosis due to mutations in TCIRG1 gene.Stem Cell Res. 2020 Jan;42:101660. doi: 10.1016/j.scr.2019.101660. Epub 2019 Nov 20.
• [4] Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7. Am J Med Genet A. 2012 Apr;158A(4):909-16. doi: 10.1002/ajmg.a.35264. Epub 2012 Mar 14.
• [5] Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007 Aug;39(8):960-2. doi: 10.1038/ng2076. Epub 2007 Jul 15.
• [6] Two novel CAII mutations causing carbonic anhydrase II deficiency syndrome in two unrelated Chinese families.Metab Brain Dis. 2015 Aug;30(4):989-97. doi: 10.1007/s11011-015-9660-6. Epub 2015 Feb 27.
• [7] Osteopetrosis: genetics, treatment and new insights into osteoclast function.Nat Rev Endocrinol. 2013 Sep;9(9):522-36. doi: 10.1038/nrendo.2013.137. Epub 2013 Jul 23.
• [8] The determination of osteopetrotic phenotypes by selective inactivation of red cell carbonic anhydrase isoenzymes.Clin Chim Acta. 1985 Nov 15;152(3):347-54. doi: 10.1016/0009-8981(85)90110-x.
• [9] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [10] New insights into the pathogenesis of renal tubular acidosis--from functional to molecular studies.Pediatr Nephrol. 2000 Oct;14(12):1121-36. doi: 10.1007/s004670000407.
• [11] SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.J Bone Miner Res. 2013 May;28(5):1041-9. doi: 10.1002/jbmr.1849.
• [12] An SNX10 mutation causes malignant osteopetrosis of infancy. J Med Genet. 2012 Apr;49(4):221-6. doi: 10.1136/jmedgenet-2011-100520.
• [13] Novel CLCN7 mutations cause autosomal dominant osteopetrosis typeII and intermediate autosomal recessive osteopetrosis.Mol Med Rep. 2019 Jun;19(6):5030-5038. doi: 10.3892/mmr.2019.10123. Epub 2019 Apr 3.
• [14] Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families.Acta Pharmacol Sin. 2017 Nov;38(11):1456-1465. doi: 10.1038/aps.2017.108. Epub 2017 Aug 17.
• [15] Structure of human SNX10 reveals insights into its role in human autosomal recessive osteopetrosis.Proteins. 2014 Dec;82(12):3483-9. doi: 10.1002/prot.24689. Epub 2014 Oct 1.