Details of Disease

General Information of Disease (ID: DISMGH8F)

• Disease Name: Leber congenital amaurosis
• Synonyms: congenital absence of the rods and cones; congenital retinal blindness; Leber's congenital tapetoretinal degeneration; Leber's congenital tapetoretinal dysplasia; Leber's disease; Leber's amaurosis; LCA; Leber's congenital amaurosis; Leber congenital amaurosis; amaurosis congenita of Leber
• Disease Class: 9B70: Inherited retinal dystrophy
• Definition: Leber congenital amaurosis (LCA) is a retinal dystrophy defined by blindness and responses to electrophysiological stimulation (Ganzfeld electroretinogram (ERG)) below threshold, associated with severe visual impairment within the first year of life.
• Disease Hierarchy:
  DIS2BIP8: Congenital nervous system disorder
  DISGGL77: Inherited retinal dystrophy
  DISMGH8F: Leber congenital amaurosis
• ICD Code:
  ICD-11: ICD-11: 9B70
  ICD-10: ICD-10: H35.5
  Expand ICD-11: '9B70
  Expand ICD-10: 'H35.5
• Disease Identifiers:
  MONDO ID: MONDO_0018998
  MESH ID: D057130
  UMLS CUI: C0339527
  MedGen ID: 137922
  Orphanet ID: 65
  SNOMED CT ID: 193413001

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 4 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
QLT-091001	DMZI4OV	Phase 2/3	NA	[1]
Sepofarsen	DM31L9K	Phase 2/3	Oligonucleotide	[2]
AAV-RPE65	DMAH6UJ	Phase 1/2	Gene therapy	[3]
Leber's congenital amaurosis gene therapy	DMFHV9L	Phase 1/2	NA	[1]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 49 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
TULP1	OTHGHV6D	Supportive	Autosomal dominant	[4]
USP45	OT0KSON1	Supportive	Autosomal dominant	[5]
CCT2	OTW1VV4E	Limited	Autosomal recessive	[20]
CDHR1	OT1ORXCM	Limited	CausalMutation	[7]
CLUAP1	OTESP4WL	Limited	Autosomal recessive	[21]
CRB2	OTG0L2CE	Limited	Biomarker	[22]
MYO7A	OTBZSPEL	Limited	Genetic Variation	[23]
NXNL1	OT92AILF	Limited	Unknown	[24]
PRPF8	OTU39JZI	Limited	Genetic Variation	[25]
RGS9	OTRA1LOC	Limited	CausalMutation	[7]
RPGRIP1L	OT6Z069I	Limited	Biomarker	[26]
AIPL1	OT4VBD78	Supportive	Autosomal dominant	[8]
CEP290	OTVN52VH	Supportive	Autosomal dominant	[8]
CRB1	OTXYUNG0	Supportive	Autosomal dominant	[8]
CRX	OTH435SV	Supportive	Autosomal dominant	[27]
GDF6	OTERXWJU	Supportive	Autosomal dominant	[28]
GUCY2D	OT81UJI0	Supportive	Autosomal dominant	[8]
IFT140	OT6KO5FH	Supportive	Autosomal dominant	[29]
IMPDH1	OT6QGM5Y	Supportive	Autosomal dominant	[9]
IQCB1	OTYQ28V9	Supportive	Autosomal dominant	[30]
KCNJ13	OTG1CNND	Supportive	Autosomal dominant	[31]
LCA5	OTQTCUWS	Supportive	Autosomal dominant	[32]
LRAT	OTB7CJKY	Supportive	Autosomal dominant	[33]
NMNAT1	OTGJH9XH	Supportive	Autosomal dominant	[18]
PCYT1A	OTMH0YLN	Supportive	Autosomal dominant	[19]
RD3	OT2L9Y6M	Supportive	Autosomal dominant	[34]
RDH12	OTELFRRJ	Supportive	Autosomal dominant	[35]
RPE65	OTHS41XM	Supportive	Autosomal dominant	[10]
RPGRIP1	OTABESO9	Supportive	Autosomal dominant	[16]
SPATA7	OT78G2IH	Supportive	Autosomal dominant	[36]
CABP4	OTL0TRR5	moderate	Genetic Variation	[37]
GUCA1B	OT85S0J3	moderate	Genetic Variation	[38]
GUCY2F	OTVRTQQ1	moderate	Biomarker	[39]
HSD17B6	OTSB55D2	moderate	Biomarker	[11]
LPCAT1	OTCV7AGV	moderate	Biomarker	[40]
ND4	OT4RQVAA	moderate	Genetic Variation	[41]
NRL	OT65MFKQ	moderate	Genetic Variation	[42]
NUB1	OTWA6RTX	moderate	Biomarker	[43]
PDE6B	OTOJMB1V	moderate	Genetic Variation	[44]
PSMD13	OTNQ351N	moderate	Genetic Variation	[45]
SP4	OTWB30IZ	moderate	Genetic Variation	[46]
ELOVL4	OT2M9W26	Strong	Genetic Variation	[47]
IMPG1	OT12HBL0	Strong	Biomarker	[48]
IMPG2	OTFPSJ0T	Strong	Altered Expression	[48]
NINL	OTWIK6HT	Strong	Biomarker	[49]
OTX2	OTTV05B1	Strong	Genetic Variation	[50]
PRPH	OT6VUH78	Strong	Genetic Variation	[51]
PRPH2	OTNH2G5H	Strong	Genetic Variation	[51]
SLC7A14	OT07YJW4	Strong	Genetic Variation	[52]

This Disease Is Related to 16 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
ABCA4	TTLB52K	Limited	Genetic Variation	[6]
CNGB3	TT0LJCG	Limited	CausalMutation	[7]
GRM6	TTWRP2F	Limited	CausalMutation	[7]
USH2A	TTVCLLA	Limited	Genetic Variation	[7]
CEP290	TT3XBOV	Supportive	Autosomal dominant	[8]
GUCY2D	TTWNFC2	Supportive	Autosomal dominant	[8]
IMPDH1	TT3GRLK	Supportive	Autosomal dominant	[9]
RPE65	TTBOH16	Supportive	Autosomal dominant	[10]
ADH7	TT3LE7P	moderate	Biomarker	[11]
CNTLN	TT8MI6U	moderate	Genetic Variation	[12]
SLC19A2	TT2A1DZ	moderate	Genetic Variation	[13]
CEP290	TT3XBOV	Strong	Genetic Variation	[7]
CNGA3	TTW0QOV	Strong	Genetic Variation	[14]
IMPDH1	TT3GRLK	Strong	GermlineCausalMutation	[8]
PNPLA6	TTWAQU2	Strong	Genetic Variation	[15]
RPGR	TTHBDA9	Strong	Genetic Variation	[16]

This Disease Is Related to 4 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NMNAT1	DE4D159	Limited	Genetic Variation	[17]
NMNAT1	DE4D159	Supportive	Autosomal dominant	[18]
PCYT1A	DEQYXD4	Supportive	Autosomal dominant	[19]
PCYT1A	DEQYXD4	Definitive	GermlineCausalMutation	[19]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] ClinicalTrials.gov (NCT04855045) An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene. (BRIGHTEN). U.S. National Institutes of Health.
• [3] ClinicalTrials.gov (NCT02781480) Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (OPTIRPE65). U.S. National Institutes of Health.
• [4] Novel TULP1 mutation causing leber congenital amaurosis or early onset retinal degeneration. Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5160-7. doi: 10.1167/iovs.06-1013.
• [5] Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. J Med Genet. 2019 May;56(5):325-331. doi: 10.1136/jmedgenet-2018-105709. Epub 2018 Dec 20.
• [6] Detecting genetic variations in hereditary retinal dystrophies with next-generation sequencing technology.Mol Vis. 2014 Apr 26;20:553-60. eCollection 2014.
• [7] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [8] Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015 Feb 16;3(2):112-24. doi: 10.12998/wjcc.v3.i2.112.
• [9] Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006 Jan;47(1):34-42. doi: 10.1167/iovs.05-0868.
• [10] RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis. Ophthalmic Genet. 2016 Jun;37(2):161-9. doi: 10.3109/13816810.2014.991931. Epub 2014 Dec 12.
• [11] RDH12, a retinol dehydrogenase causing Leber's congenital amaurosis, is also involved in steroid metabolism.J Steroid Biochem Mol Biol. 2007 May;104(3-5):190-4. doi: 10.1016/j.jsbmb.2007.03.015. Epub 2007 Mar 23.
• [12] Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis.Hum Gene Ther. 2018 Jan;29(1):42-50. doi: 10.1089/hum.2017.049. Epub 2017 Jul 5.
• [13] Leber's congenital amaurosis as the retinal degenerative phenotype in thiamine responsive megaloblastic anemia: a case report.Ophthalmic Genet. 2014 Jun;35(2):119-24. doi: 10.3109/13816810.2013.793363. Epub 2013 May 2.
• [14] Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy. Eur J Hum Genet. 2015 Apr;23(4):473-80. doi: 10.1038/ejhg.2014.136. Epub 2014 Jul 23.
• [15] Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.Nat Commun. 2015 Jan 9;6:5614. doi: 10.1038/ncomms6614.
• [16] Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet. 2001 Aug;9(8):561-71. doi: 10.1038/sj.ejhg.5200689.
• [17] NMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype.Exp Eye Res. 2018 Aug;173:32-43. doi: 10.1016/j.exer.2018.04.010. Epub 2018 Apr 17.
• [18] NMNAT1 mutations cause Leber congenital amaurosis. Nat Genet. 2012 Sep;44(9):1040-5. doi: 10.1038/ng.2361. Epub 2012 Jul 29.
• [19] Mutations in the PCYT1A gene are responsible for isolated forms of retinal dystrophy. Eur J Hum Genet. 2017 May;25(5):651-655. doi: 10.1038/ejhg.2017.23. Epub 2017 Mar 8.
• [20] CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability. Sci Rep. 2016 Sep 20;6:33742. doi: 10.1038/srep33742.
• [21] Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genet Med. 2016 Oct;18(10):1044-51. doi: 10.1038/gim.2015.205. Epub 2016 Jan 28.
• [22] Loss of CRB2 in Mller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype.Hum Mol Genet. 2019 Jan 1;28(1):105-123. doi: 10.1093/hmg/ddy337.
• [23] Assessment of different virus-mediated approaches for retinal gene therapy of Usher 1B.Adv Exp Med Biol. 2014;801:725-31. doi: 10.1007/978-1-4614-3209-8_91.
• [24] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [25] Histopathologic-genotypic correlations in retinitis pigmentosa and allied diseases.Ophthalmic Genet. 2005 Jun;26(2):91-100. doi: 10.1080/13816810590968032.
• [26] Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat Genet. 2007 Jul;39(7):882-8. doi: 10.1038/ng2069. Epub 2007 Jun 10.
• [27] Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum Mol Genet. 1999 Feb;8(2):299-305. doi: 10.1093/hmg/8.2.299.
• [28] Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies. Hum Mol Genet. 2013 Apr 1;22(7):1432-42. doi: 10.1093/hmg/dds560. Epub 2013 Jan 9.
• [29] Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum Genet. 2015 Oct;134(10):1069-78. doi: 10.1007/s00439-015-1586-x. Epub 2015 Jul 28.
• [30] IQCB1 mutations in patients with leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011 Feb 11;52(2):834-9. doi: 10.1167/iovs.10-5221.
• [31] Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet. 2011 Jul 15;89(1):183-90. doi: 10.1016/j.ajhg.2011.06.002.
• [32] Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nat Genet. 2007 Jul;39(7):889-95. doi: 10.1038/ng2066. Epub 2007 Jun 3.
• [33] Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis. Am J Ophthalmol. 2006 Oct;142(4):702-4. doi: 10.1016/j.ajo.2006.04.057.
• [34] Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet. 2006 Dec;79(6):1059-70. doi: 10.1086/510021. Epub 2006 Oct 23.
• [35] Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis. Am J Hum Genet. 2004 Oct;75(4):639-46. doi: 10.1086/424889. Epub 2004 Aug 20.
• [36] Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa. Am J Hum Genet. 2009 Mar;84(3):380-7. doi: 10.1016/j.ajhg.2009.02.005. Epub 2009 Mar 5.
• [37] A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.Mol Vis. 2010 Feb 10;16:207-12.
• [38] Evaluating the role of retinal membrane guanylyl cyclase 1 (RetGC1) domains in binding guanylyl cyclase-activating proteins (GCAPs).J Biol Chem. 2015 Mar 13;290(11):6913-24. doi: 10.1074/jbc.M114.629642. Epub 2015 Jan 23.
• [39] AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis.Hum Gene Ther. 2013 Feb;24(2):189-202. doi: 10.1089/hum.2012.193.
• [40] Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15523-8. doi: 10.1073/pnas.1002897107. Epub 2010 Aug 16.
• [41] Homoplasmic and exclusive ND4 gene mutation in Japanese pedigrees with Leber's disease.Invest Ophthalmol Vis Sci. 1993 Mar;34(3):488-95.
• [42] Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL.Hum Mutat. 2010 Jun;31(6):E1472-83. doi: 10.1002/humu.21268.
• [43] Abolished interaction of NUB1 with mutant AIPL1 involved in Leber congenital amaurosis.Biochem Biophys Res Commun. 2004 May 7;317(3):768-73. doi: 10.1016/j.bbrc.2004.03.108.
• [44] Linkage studies and mutation analysis of the PDEB gene in 23 families with Leber congenital amaurosis.Hum Mutat. 1992;1(6):478-85. doi: 10.1002/humu.1380010605.
• [45] Temperature-sensitive retinoid isomerase activity of RPE65 mutants associated with Leber Congenital Amaurosis.J Biochem. 2015 Aug;158(2):115-25. doi: 10.1093/jb/mvv028. Epub 2015 Mar 9.
• [46] Association of the Asn306Ser variant of the SP4 transcription factor and an intronic variant in the beta-subunit of transducin with digenic disease.Mol Vis. 2007 Feb 28;13:287-92.
• [47] Evaluation of the ELOVL4 gene in patients with autosomal recessive retinitis pigmentosa and Leber congenital amaurosis.Mol Vis. 2003 Feb 18;9:49-51.
• [48] Organization of the human IMPG2 gene and its evaluation as a candidate gene in age-related macular degeneration and other retinal degenerative disorders. Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3123-9.
• [49] Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein.Hum Mol Genet. 2009 Jan 1;18(1):51-64. doi: 10.1093/hmg/ddn312. Epub 2008 Sep 30.
• [50] A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction.Mol Vis. 2009 Nov 21;15:2442-7.
• [51] Peripherin mutations cause a distinct form of recessive Leber congenital amaurosis and dominant phenotypes in asymptomatic parents heterozygous for the mutation. Br J Ophthalmol. 2016 Feb;100(2):209-15. doi: 10.1136/bjophthalmol-2015-306844. Epub 2015 Jun 10.
• [52] Phenotypic variability of SLC7A14 mutations in patients with inherited retinal dystrophy.Ophthalmic Genet. 2019 Apr;40(2):118-123. doi: 10.1080/13816810.2019.1586964. Epub 2019 Mar 29.