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LOVD - Variant listings for OTX2

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+/+ 00 - 47 kb deletion of OTX2 promoter region - - - - OTX2_00039 - - - - - - Deletion - CGH - - Deletion of OTX2 promoter region Patient 21 Microphthalmia [21353197], United Kingdom (Great Britain):Edinburgh DNA SEQ Deletion inherited from healthy father 2 - - Familial Sporadic - - - Microphthalmia (right eye more severely affected). Optic nerves and chiasma absent by MRI. Enlargement of the cisterna magna. -
+/+ 01 c.252delC c.81delC - p.(Ser28Profs*23) Predicted frameshift leading to PTC - NMD likely Translation unlikely OTX2_00003 Exon 81 GCACCC C - TCCGTG Deletion N-terminal domain Direct Sequencing - 0/188 Mutant allele inherited from unaffected mosaic mother Ragge 2005 Patient 3 Microphthalmia Ragge 2005 Patient 3 [15846561], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - female Familial Sporadic Y - n/a Bilateral severe microphthalmia (no vision). Mutant allele inherited from unaffected mosaic mother. Subsequent pregnancy terminated - affected foetus carried same mutation -
-/- 01 - c.85G>A - p.(Val29Met) Val (gug) > Met (aug) predicted Predicted missense substitution of conserved N-terminal residue OTX2_00022 Exon 85 CCCTCC G A TGGGCT Substitution N-terminal domain Amplicon Melting Analysis - - Same variant in unaffected father Wyatt 2008 DBS Donnai-Barrow Syndrome Wyatt 2008 DBS [18781617] [18553518], United Kingdom (Great Britain):Edinburgh DNA AMA Causative Donnai-Barrow syndrome (Facio-oculo-acoustico-renal syndrome) mutation already identified in this patient (LRP2 mutation on chromosome 2) 1 - male Familial Sporadic - - Y Unaffected father has same OTX2 variant Facio-oculo-acoustico-renal syndrome caused by LRP2 mutation
+/+ 01 c.264C>G c.93C>G - p.(Tyr31*) Tyr (uac) > Stop (uag) predicted. NMD likely NMD predicted - protein synthesis unlikely OTX2_00018 Exon 93 GGGCTA C G CCGGCC Substitution N-terminal domain Amplicon Melting Analysis - - - Wyatt 2008 Case 3 Microphthalmia Wyatt 2008 Case 3 [18781617], United Kingdom (Great Britain):Edinburgh DNA AMA - 1 - female Sporadic Sporadic - - - Right nystagmus, left microphthalmia. -
-/- 01 c.268+12C>T c.97+12C>T - p.= Probable neutral intronic substitution No effect predicted OTX2_00009 Intron 97 TGAGCC C T TGCTGC Substitution - Direct Sequencing - C=0.981/T=0.019 SNP frequency assessed in 188 control chromosomes Ragge 2005 Control None Ragge 2005 Control [15846561] , United Kingdom (Great Britain):Edinburgh DNA SEQ rs28757218 in dbSNP 1 - - - - - - N - -
-/- 01 c.269-70C>A c.98-70C>A - p.= No effect on transcription expected No change expected OTX2_00010 Intron 98 - C A - Substitution - Direct Sequencing - - - Ragge 2005 Control - Ragge 2005 Control [15846561] , United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - - - - - - N - -
+/+ 02 - c.106delC - p.(Arg36Glyfs*15) Frame-shifting deletion leading to PTC Truncated protein predicted OTX2_00041 Exon 106 ACCCCC C - GGAAAC Deletion N-terminal domain Direct Sequencing - - - Family B II-1 Otocephaly Chassaing 2012 [22577225], United Kingdom (Great Britain):Edinburgh DNA SEQ De novo mutation (absent from both parents) 1 - female Sporadic Sporadic - - - Otocephaly (tubular nose, microstomia, agnathia, low-set ears) -
+/+ 02 - c.106dupC - p.(Arg36Profs*52) Frame-shifting insertion predicted to create PTC Truncated protein predicted OTX2_00019 Exon 106 CCCCCC - C GGAAAC Duplication N-terminal domain Amplicon Melting Analysis - - Probable replication slippage Wyatt 2008 Case 4 Microphthalmia Wyatt 2008 Case 4 [18781617], United Kingdom (Great Britain):Edinburgh DNA AMA Same mutation in 2 affected sibs suggests inheritance from phenotypically normal but genetically mosaic parent. Parental blood and buccal DNA normal - mutation may be confined to germline. Protein change published as p.R36Pfs87X 1 - male - - - - - Case 4 has right microphthalmia (left eye normal). His younger brother (case 5) has right anopththalmia, left coloboma. Both boys otherwise normal -
+/+ 02 c.288delCC c.117_118delCC - p.(Arg40Glyfs*47) Predicted frameshifting deletion leading to PTC in last coding exon Truncated protein predicted OTX2_00005 Exon 117 ACAGCG CC - GGGAGA Deletion Homeodomain Direct Sequencing - 0/188 - Ragge 2005 Patient 5 Anophthalmia Ragge 2005 Patient 5 [15846561], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation inherited from unaffected mother - allele may have low penetrance or act digenically 1 - male Familial Sporadic Y - n/a Bilateral anophthalmia. Hypoplastic optic nerves, optic chiasm and anterior commissure by MRI. Delayed speech and motor development. Mother with same mutation is normal -
+/+ 02 - c.136dupA - p.(Thr46Asnfs*42) Frame-shifting duplication creates PTC in last exon (exon 3) Truncated protein predicted OTX2_00032 Exon 136 CGTTCA - A CTCGGG Duplication Homeodomain Direct Sequencing - 0/192 - Patient 1A Bilateral microphthalmia [20486942], United Kingdom (Great Britain):Edinburgh DNA SEQ Father (Patient 1B) with same mutation has unilateral left microphthalmia and right retinal defects 2 - female Familial Familial - - - Bilateral microphthalmia, severe optic nerve hypoplasia. Sacral dimple, anteriorly placed anus. Normal development. -
+/+ 02 - c.203G>C - p.(Arg68Pro) Arg (cga) > Pro (cca) predicted. Missense change in homeodomain affects activation of the IRBP promoter but not the POU1F1 promoter. OTX2_00037 Exon 203 TCATGC G C AGAGGA Substitution Homeodomain Direct Sequencing - - - Sister of propositus Anophthalmia, microphthalmia [22268617], United Kingdom (Great Britain):Edinburgh DNA SEQ Paper describes father, uncle and sister of propositus but the phenotype of the propositus is not given. Father of propositus: right microphthalmia. Uncle of propositus: left microphthalmia. Neither has developmental delay or pituitary anomalies. The SOX2 and PAX6 genes were normal in this family. 3 Chinese female Familial Familial - - - Right anophthalmia, left microphthalmia. No extra-ocular anomalies; no developmental delay; no pituitary problems. -
+/+ 02 - c.214_217delGCACinsCA
    + c.734C>T
- p.(Ala72Hisfs*15) Predicted frame-shifting deletion leading to PTC PTC is in last exon - truncated protein predicted. Mutant protein has severely decreased transactivation activity OTX2_00026 Exon 214 GAGGTG GCAG CA TGAAAA Insertion/Deletion - Direct Sequencing - 0/100 This variant has arisen de novo. Patient also has an apparently neutral missense change Dateki 2010 Case 2 Microphthalmia [19965921] DNA SEQ Patient has a de novo pathological insertion/deletion and an inherited neutral missense change 1 94 Japanese patients female One change de novo; one change inherited Sporadic - - - Bilateral microphthalmia. Normal pituitary function -
+/+ 02 - c.221_236del16
    + c.532A>T
- p.(Lys74Serfs*30) Frame-shifting deletion leading to PTC PTC is in last exon - truncated protein predicted. Mutant protein has impaired transactivation activity OTX2_00024 Exon 221 CACTGA AAATCAACTTGCCCGA - GTCGAG Deletion Homeodomain Direct Sequencing - 0/100 Patient also has an apparently neutral missense change Dateki 2010 Case 1 Anophthalmia / microphthalmia [19965921], United Kingdom (Great Britain):Edinburgh DNA SEQ Patient has two variants, one pathological and one apparently neutral 1 94 Japanese patients male Sporadic Sporadic - - - Right anophthalmia; left microphthalmia; developmental delay; pituitary hypoplasia by MRI -
+/+ 02 - c.234delC - p.(Glu79Serfs*30) Frame-shifting deletion predicted PTC predicted OTX2_00044 Exon 234 CTTGCC C - GAGTCG Deletion Homeodomain Direct Sequencing - - - Case ID 2896 Anophthalmia (24498598), United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 German male - Sporadic - - - Bilateral anophthalmia, absent optic tract by MRI, delayed development and growth, sleep disturbance Left microtia
+/+ 02 - c.247_249dupCAG - p.(Gln83dup) Duplication of glutamine codon (cag) predicted Duplication of glutamine predicted OTX2_00058 Exon 247 GTGCAG - CAG /GTAGGG Duplication Homeodomain Direct Sequencing - - Variant associated with highly variable phenotype III:2 Velopharyngeal insufficiency [25589041], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation also detected in patient's healthy father II:1 and mother II:2, and a sibling foetus with agnathia-otocephaly complex 1 Caucasian female Familial Sporadic - - - Small mandible, normal ears and velopharyngeal insufficiency due to a short hemi-palate. -
+?/+? 02 - c.249G>C r.(spl)? p.(Gln83His)/p.? Gln (cag) > His (cac) predicted. Last base of exon substituted - may affect splicing Outcome unknown without RNA analysis OTX2_00060 Exon 249 GGTGCA G C /GTAGGG Substitution Homeodomain Direct Sequencing - - - Slavotinek 2015 Anophthalmia {PMID[25457163]), United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - female - - - - - Bilateral anophthalmia, growth delay, intellectual disability, autism -
+/+ 02 - c.249G>T r.(spl)? p.(Gln83His)/p.? Gln (cag) > His (cau) predicted. Last base of exon substituted - may affect splicing Outcome unknown without RNA analysis OTX2_00045 Exon 249 GGTGCA G T /GTAGGG Substitution Homeodomain Direct Sequencing - - - Case ID 3197 Unilateral anophthalmia (24498598), United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 United Arab Emirates female - Sporadic Yes No - Right anophthalmia; left eye normal. -
+?/+? 03 - c.254G>T - p.(Trp85Leu) Trp (ugg) > Leu (uug) predicted. Missense mutation in homeodomain. OTX2_00064 Exon 254 GTAT G T GTTTAA Substitution HD Other - - Exome sequencing Somashekar et al III-1 Unilateral microphthalmia [28388256], United Kingdom (Great Britain):Edinburgh DNA Other Mutation identified by exome sequencing. Mutation inherited from very mildly affected mother with strabismus and ptosis. Mutation also present in other family members with unilateral and bilateral microphthalmia. 1 - male Familail Familial - - - Severe unilateral microphthalmia -
+/+ 03 c.436C>G c.265C>G - p.(Arg89Gly) Arg (cga) > Gly (gga) predicted Predicted missense change in homeodomain. Mutant protein has reduced DNA binding activity OTX2_00002 Exon 265 AAGAAT C G GAAGAG Substitution Homeodomain - TaqI(-) 0/188 - Ragge 2005 Patient 2 Microphthalmia Ragge 2005 Patient 2 [15846561] [16607563], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - male Sporadic Sporadic Y - Y Bilateral microphthalmia (no vision), optic nerves and chiasm absent by MRI -
+/+ 03 c.436C>G c.265C>T - p.(Arg89*) Arg (cga) > Ter (tga) predicted Predicted nonsense change in homeodomain OTX2_00036 Exon 265 AAGAAT C T GAAGAG Substitution Homeodomain Direct Sequencing TaqI(-) - - Index case 31 Bilateral anophthalmia [20494911], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 50 Mexican subjects unknown unknown - - - - Bilateral anophthalmia. No systemic anomalies -
+/+ 03 - c.265C>T - p.(Arg89*) Arg (cga) > Ter (uga) predicted. Protein truncation predicted OTX2_00052 Exon 265 AAGAAT C T GAAGAG Substitution c.289C>T in NM_021728.2 Direct Sequencing - - - Chassaing 2013 Patient 21 Unilateral anophthalmia [24033328], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - male - Sporadic - - - Pregnancy terminated at 22 weeks of gestation after detection of unilateral anophthalmia. -
+/+ 03 - c.265C>T
    + c.501C>G
- p.(Arg89*) Nonsense mutation Arg (cga) > Ter (tga) predicted Truncated protein predicted OTX2_00055 Exon 265 AAGAAT C T GAAGAG Substitution - Direct Sequencing - - c.289C>T in NM_021728.2 Case 4 Patat 2013 Otocephaly-dysgnathia complex (24167467) (240333280), United Kingdom (Great Britain):Edinburgh DNA SEQ Proband has inherited two OTX2 variants, c.264C>T from mother (Patient 22 in Chassaing 2013) with unilateral microphthalmia and c.501C>G from healthy father 1 - male Familial Familial - - - Agnathia, astomia, aglossia; bilateral microphthalmia; absent optic chiasma and pituitary gland -
+/+ 03 - c.266G>C - p.(Arg89Pro) Arg (cga) > Pro (cca) predicted Missense mutation in HD predicted. Mutant protein shows greatly reduced DNA binding and reporter activation OTX2_00061 Exon 288 AGAATC G C AAGAGC Substitution HD Direct Sequencing - - Mutation not present in 150 controls or variation databases Shimada 2016 Microphthalmia, CPHD, Agenesis of internal carotid artery [27299576], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation inherited from clinically normal father 1 - male Familial Sporadic - - - Complex phenotype including bilateral microphthalmia, heart anomalies, agenesis of the left internal carotid artery, frontal bossing, left choanal stenosis, genital anomalies, hypothyroidism, hypoglycaemia -
+/+ 03 - c.270A>T - p.(Arg90Ser) Arg (aga) > Ser (agu) predicted Missense change in homeodomain predicted. Mutant protein has greatly reduced DNA binding and trans-activation activities OTX2_00031 Exon 270 TCGAAG A T GCTAAG Substitution Homeodomain Direct Sequencing - - - III-3 Anophthalmia, growth hormone deficiency [20396904], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation inherited from father (II-2) with healthy eyes. Younger brother (III-4) has bilateral anophthalmia. Mutation appears to have variable penetrance in extended family. 2 Sephardic Jewish male Familial Familial - - Yes Unilateral (right) anophthalmia, short stature, isolated growth hormone deficiency. Abnormal pituitary gland by MRI. Normal psychomotor development. -
+/+ 03 - c.276_294del19 - p.(Lys92Asnfs*11) Frame-shifting deletion predicted Truncated protein predicted OTX2_00046 Exon 276 AGCTAA GTGCCGCCAACAACAGCAA - CAACAG Deletion C-terminal domain Direct Sequencing - - - Case ID 2867 Anophthalmia/microphthalmia (24498598), United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - female Familial Sporadic Yes No - Right anophthalmia; left microphthalmia, microcornea and retinal coloboma. Developmental delay; sleep disturbance Talipes equinovarus
+/+ 03 - c.289C>T - p.(Gln97*) Gln (cag) > Ter (uag) predicted. Protein truncation predicted immediately after homeodomain OTX2_00020 Exon 289 CAACAA C T AGCAAT Substitution C-terminal domain Amplicon Melting Analysis - - - Wyatt 2008 Case 6 Microphthalmia Wyatt 2008 Case 6 [18781617], United Kingdom (Great Britain):Edinburgh DNA AMA Mutation inherited from reportedly affected father (described as having reduced vision in one eye but not available for examination) 1 - male Familial Familial - - - Case 6 (male) has bilateral extreme microphthalmia. His twin sister (case 7) has right iris coloboma and left retinal coloboma -
+/+ 03 - c.292delC - p.(Gln98Asnfs*11) Frame-shifting deletion leading to PTC Truncated protein predicted OTX2_00040 Exon 292 CAACAG C - AACAAC Deletion C-terminal domain Direct Sequencing - - - Family A IV-7 Anophthalmia Chassaing 2012 2013 [22577225] [24033328], United Kingdom (Great Britain):Edinburgh DNA SEQ Proband IV-7 is from a large family affected by variable craniofacial and ocular malformations including microphthalmia, anophthalmia, micrognathia and otocephaly. All affected individuals have the same mutation 1 - male Familial Familial - - - Bilateral anophthalmia, intellectual disability. -
+/+ 03 c.466C>T c.295C>T - p.(Gln99*) Predicted nonsense mutation: Gln (caa) > Ter (uaa) Truncated protein predicted OTX2_00006 Exon 295 CAGCAA C T AACAGC Substitution C-terminal domain Direct Sequencing - 0/188 Variant inherited from normal father Ragge 2005 Patient 6 Anophthalmia Ragge 2005 Patient 6 [15846561], United Kingdom (Great Britain):Edinburgh RNA SEQ Variant inherited from unaffected father - possible variable penetrance or digenic effect 1 - male Familial Sporadic Y - n/a Bilateral anophthalmia, severe seizures, severe learning disability. Father with same mutation is unaffected -
+/+ 03 - c.313C>T - p.(Gln105*) Gln (caa) > Ter (uaa) predicted Truncated protein predicted OTX2_00033 Exon 313 GGAGGT C T AAAACA Substitution C-terminal domain Direct Sequencing - 0/384 - Patient 2 Bilateral anophthalmia [20486942], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - female Sporadic Sporadic - - - Bilateral clinical anophthalmia, optic nerve aplasia. Normal growth. Autism spectrum disorder, severe feeding difficulties. Cold sweats and racing pulse (Wolf-Parkinson-White syndrome)
+/+ 03 - c.313C>T - p.(Gln105*) Gln (caa) > Ter (uaa) predicted Truncated protein predicted OTX2_00038 Exon 313 GGAGGT C T AAAACA Substitution - Direct Sequencing - - - 792-508 Anophthalmia [22204637] , United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation identified by next-generation parallel sequencing of 9 anophthalmia/microphthalmia genes. Mutation absent in normal parents. 1 - - Sporadic Sporadic - - - Anophthalmia; feeding disorder (unclear if related or not) -
+/+ 03 - c.373_374delAG - p.(Gly126Trpfs*11) Frame-shifting deletion predicted to create PTC Truncated protein predicted OTX2_00021 Exon 373 TCAGAG AG - TGGAAC Deletion C-terminal domain Amplicon Melting Analysis - - Replication slippage likely Wyatt 2008 Case 8 Anophthalmia Wyatt 2008 Case 8 [18781617], United Kingdom (Great Britain):Edinburgh DNA AMA DNA change published as c.371_372delAG. Protein change published as p.E124Efs135X 1 - male Familial Sporadic - - - Bilateral anophthalmia; mild developmental delay. Mutation inherited from unaffected mother -
-?/-? 03 c.568C>A c.397C>A - p.(Pro133Thr) Missense change predicted: Pro (ccc) > Thr (acc) Mutation affects last residue of highly conserved SGQFTP motif. No effect on DNA binding, nuclear localisation or transcriptional activity OTX2_00007 Exon 397 TTCACT C A CCCCCT Substitution SGQFTP motif Direct Sequencing - 0/328 - Ragge 2005 Patient 7 Microphthalmia Ragge 2005 Patient 7 [15846561] [16607563] , United Kingdom (Great Britain):Edinburgh DNA SEQ Patient has a missense mutation in a highly conserved motif but same change is present in normal mother and brother 1 - female Sporadic Familial Y - Y Bilateral microphthalmia with retinal detachment (no vision); left sclerocornea. Same DNA change in unaffected brother and mother -
-?/-? 03 c.571C>G c.400C>G - p.(Pro134Ala) Pro (ccc) > Ala (gcc) predicted Missense change predicted. No effect on DNA binding, nuclear localisation or transcriptional activity OTX2_00008 Exon 400 ACTCCC C G CCTCTA Substitution C-terminal domain Direct Sequencing - 0/328 Variant absent from affected mother Ragge 2005 Patient 8 Anophthalmia Ragge 2005 Patient 8 [15846561] [16607563], United Kingdom (Great Britain):Edinburgh DNA SEQ Probable neutral variant - absent from similarly affected mother. Father unavailable 1 - male Unknown Familial Y - - Unilateral anophthalmia; attention deficit disorder. Variant absent from similarly affected mother -
+/+? 03 - c.401C>G - p.(Pro134Arg) Pro (ccc) > Arg (cgc) predicted Mutant protein shows impaired transactivation activity OTX2_00042 Exon 401 CTCCCC C G CTCTAG Substitution C-terminal domain Direct Sequencing - - - Del Blanco et al Combined pituitary hormone deficiency Del Blanco 2012 [22715480], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 92 Dutch patients with pituitary disorders unknown unknown - - - - Combined pituitary hormone deficiency; unilateral optic nerve hypoplasia -
+/+ 03 - c.402delC - p.(Ser135Leufs*43) Frame-shifting deletion leading to PTC Truncated protein predicted OTX2_00062 Exon 402 TCCCCC C - TCTAGC Deletion - Direct Sequencing - - - Lonero 2016 Microphthalmia, GH deficiency [26974134], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation not present in parents 1 Italian female Sporadic Sporadic - - - Severe right microphthalmia, mild left macular dystrophy, short stature, GH deficiency, ectopic posterior pituitary. -
+/+ 03 c.573dupC c.402dupC - p.(Ser135Leufs*2) Frameshifting insertion leads to premature stop codon Truncated protein localizes to nucleus but has impaired inactivation of HESX1 and POU1F1 promoters OTX2_00012 Exon 402 CCCCCC - C TCTAGC Duplication C-terminal domain Direct Sequencing - - De novo mutation in patient Dateki 2008 Anophthalmia, GH deficiency Dateki 2008 [18628516], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation absent from both parents 1 Japanese female Sporadic Sporadic - - - Bilateral anophthalmia; short stature; partial growth hormone deficiency; developmental delay -
+/+ 03 c.575_576dupCT c.404_405dupCT - p.(Ser136Leufs*43) Frameshifting insertion creates PTC in C-terminal domain Truncated protein predicted OTX2_00015 Exon 404 CCCTCT - CT AGCACC Duplication C-terminal domain Direct Sequencing - - - Tajima 2009 OTX2 syndrome Tajima 2009 [18854396], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation absent from normal parents 1 Japanese male Sporadic Sporadic - - - Bilateral anophthalmia, combined pituitary hormone deficiency, small penis, undescended testes. Pituitary hypoplasia, optic nerve defects and Chiari malformation by MRI -
+/+ 03 - c.413C>G - p.(Ser138*) Ser (uca) > Ter (uga) predicted Truncated protein predicted OTX2_00023 Exon 413 GCACCT C G AGTCCC Substitution C-terminal domain Direct Sequencing - 0/181 - Henderson 2010 Pt 13424 Retinal dystrophy, pituitary dysfunction [19956411], United Kingdom (Great Britain):Edinburgh DNA SEQ Patient panel was first tested with an LCA microarray chip but was negative for known disease-associated variants. 1 142 patients with LCA and related anomalies male Sporadic Sporadic Yes - - Infantile onset retinal dystrophy; failure to thrive; growth hormone deficiency. Abnormal ERG results; abnormal retinal pigmentation -
+/+ 03 - c.456_457delGAinsAT - p.(Trp152*) Trp (ugg) > Ter (uga) predicted Truncated protein predicted OTX2_00034 Exon 456 TATCTG GA AT GCCCAG Insertion/Deletion SIWSPA Direct Sequencing - 0/384 - Patient 3 Anophthalmia / Microphthalmia [20486942], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - male Sporadic Sporadic - - - Right anophthalmia, left microphthalmia, bilateral optic nerve hypoplasia, absent optic chiasms. Hypopituitarism, feeding difficulties, failure to thrive, microcephaly, global developmental delay -
+/+ 03 c.635insGC c.463_464dupGC - p.(Ser156Leufs*23) Predicted frameshifting insertion leading to PTC Truncated protein predicted OTX2_00001 Exon 463 CCCAGC - GC TTCCAT Duplication C-terminal domain Direct Sequencing - 0/188 - Ragge 2005 Patient 1 Anophthalmia Ragge 2005 Patient 1 [15846561] , United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - male Sporadic Sporadic Y - n/a Right anophthalmia, left microphthalmia with chorioretinal coloboma, severe learning disability, brain anomalies by MRI -
-/- 03 - c.501C>G
    + c.265C>T
- p.(=) Ser (tcc) > Ser (tcg) predicted No effect predicted OTX2_00056 Exon 501 CACCTC C G TCTTCC Substitution - Direct Sequencing - - c.525C>G in NM_021728.2 Case 4 Patat 2013 Otocephaly-dysgnathia complex (24167467) (240333280), United Kingdom (Great Britain):Edinburgh DNA SEQ Proband has inherited two OTX2 variants, c.264C>T from mother (Patient 22 in Chassaing 2013) with unilateral microphthalmia and c.501C>G from healthy father 1 - male Familial Familial - - - Agnathia, astomia, aglossia; bilateral microphthalmia; absent optic chiasma and pituitary gland -
-/- 03 - c.532A>T
    + c.221_236del16
- p.(Thr178Ser) Thr (acc) > Ser (ucc) predicted Missense change in C-terminal domain. No effect on transactivation activity. OTX2_00025 Exon 532 CCCATG A T CCTATA Substitution C-terminal domain Direct Sequencing - 0/100 Patient also has a pathological deletion Dateki 2010 Case 1 Anophthalmia / microphthalmia [19965921], United Kingdom (Great Britain):Edinburgh DNA SEQ Patient has two variants, one pathological and one apparently neutral 1 94 Japanese patients male Sporadic Sporadic - - - Right anophthalmia; left microphthalmia; developmental delay; pituitary hypoplasia by MRI -
+/+ 03 c.708T>A c.537T>A - p.(Tyr179*) Tyr (uau) > Ter (uaa) predicted Truncated protein predicted OTX2_00004 Exon 537 GACCTA T A ACTCAG Substitution C-terminal domain Direct Sequencing - 0/188 Mutation inherited from mosaic mother Ragge 2005 Patient 4A Microphthalmia Ragge 2005 Patient 4A [15846561], United Kingdom (Great Britain):Edinburgh DNA SEQ Mutation inherited from mildly affected mosaic mother 1 - female Familial Familial - - - 4A has bilateral microphthalmia, corectopia, iris coloboma. Severe developmental delay. Brother (4B) with same mutation has mild microphthalmia. Mosaic mother has late onset retinopathy -
+/+ 03 - c.553_556dupTATA - p.(Ser186Ilefs*2) Frame-shifting duplication creates PTC Truncated protein predicted OTX2_00035 Exon 553 GTTATA - TATA GTCAAG Duplication C-terminal domain Direct Sequencing - 0/384 - Patient 4 Microphthalmia [20486942], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 - female Sporadic Sporadic - - - Left severe microphthalmia, right mild microphthalmia. Hypoplastic optic nerves, small optic chiasm, small anterior pituitary and absent posterior pituitary by MRI. Failure to thrive, microcephaly, developmental delay -
+/+ 03 - c.562G>T - p.(Gly188*) Gly (gga) > Ter (tga) predicted Truncated protein predicted. Mutant protein has reduced transactivation activity OTX2_00028 Exon 562 AGTCAA G T GATATG Substitution C-terminal domain Direct Sequencing - 0/100 - Dateki 2010 Case 3 Microphthalmia [19965921], United Kingdom (Great Britain):Edinburgh DNA SEQ No parental data available 1 94 Japanese patients male - - - - - Bilateral microphthalmia. Developmental delay. Pituitary hypoplasia; reduced pituitary hormones -
+/+ 03 - c.562G>T - p.(Gly188*) Gly (gga) > Ter (tga) predicted Truncated protein predicted. Mutant protein has reduced transactivation activity OTX2_00029 Exon 562 AGTCAA G T GATATG Substitution C-terminal domain Direct Sequencing - 0/100 - Dateki 2010 Case 4 Microphthalmia [19965921], United Kingdom (Great Britain):Edinburgh DNA SEQ No parental data available 1 94 Japanese patients male - - - - - Bilateral microphthalmia. Developmental delay. Normal pituitary function -
+/+ 03 - c.651delC - p.(Thr218Hisfs*76) - Synthesis of truncated protein predicted OTX2_00059 Exon 651 AGGGGC C - ACACTC Deletion - Direct Sequencing - - Variant not found in population databases Deml 2016 Patient 2 Anophthalmia [26130484], United Kingdom (Great Britain):Edinburgh DNA SEQ Parents and siblings unaffected but not tested genetically 1 Hispanic (El Salvador) male Sporadic - - - - Bilateral anophthalmia, short stature, intellectual disability, possible autistic spectrum disorder, cerebral palsy, facial dysmorphism, joint hypermobility, left cryptorchidism, small scrotum -
+/+ 03 c.845A>G c.674A>G - p.(Asn225Ser) Missense change Asn (aau) > Ser (agu) predicted in transcription activation domain Mutant protein binds DNA normally but has dominant negative activity in reporter activation tests OTX2_00013 Exon 674 GTACCA A G TGCAGT Substitution C-terminal domain Direct Sequencing - 0/50 - Diaczok 2008 Patient 1 Combined Pituitary Hormone Deficiency Diaczok 2008 Patient 1 [18728160], United Kingdom (Great Britain):Edinburgh DNA SEQ Sporadic case - parents apparently not tested. Mutation reported as c.698A>G (N233S), presumably using different cDNA numbering system 1 - male - Sporadic - - - Combined pituitary hormone deficiency. Pituitary hypoplastic by MRI. No ocular phenotype reported -
+/+ 03 - c.674A>G - p.(Asn225Ser) Missense change Asn (aau) > Ser (agu) predicted in transcription activation domain Mutant protein binds DNA normally but has dominant negative activity in reporter activation tests OTX2_00014 Exon 674 GTACCA A G TGCAGT Substitution C-terminal domain Direct Sequencing - 0/50 - Diaczok 2008 Patient 2 Combined Pituitary Hormone Deficiency Diaczok 2008 Patient 2 [18728160], United Kingdom (Great Britain):Edinburgh DNA SEQ Parental genotypes not reported. Mutation published as c.698A>G (N233S), presumably using an alternative cDNA numbering system 1 - female - Sporadic - - - Combined pituitary hormone deficiency. Pituitary hypoplastic by MRI. No ocular phenotype reported -
-/- 03 - c.734C>T
    + c.214_217delGCACinsCA
- p.(Ala245Val) Ala (gcu) > Val (guu) predicted Apparently neutral change. Mutant protein has normal transactivation activity OTX2_00027 Exon 734 ATGGAG C T TTCAAG Substitution C-terminal domain Direct Sequencing - 0/100 Neutral variant inherited from normal father Dateki 2010 Case 2 Microphthalmia [19965921] DNA SEQ Patient has a de novo pathological insertion/deletion and an inherited neutral missense change 1 94 Japanese patients female One change de novo; one change inherited Sporadic - - - Bilateral microphthalmia. Normal pituitary function -
?/? 03 - c.737C>A - p.(Ser246*) Ser (uca) > Ter (uaa) predicted Truncated protein predicted OTX2_00057 Exon 737 GAGCTT C A AAGCTT Substitution - Direct Sequencing - - Whole-genome sequencung Trio ID 7 Severe intellectual disability [24896178], United Kingdom (Great Britain):Edinburgh DNA SEQ De novo mutation in patient detected by whole-genome sequencing. Mutation reported as c.761C>A (NM_021728), which corresponds to c.737C>A in NM_172337.1 1 - - Sporadic Sporadic - - - Severe intellectual disability. No classical OTX2 phenotypic features. -
-/- 03 c.1051G>A c.*10G>A - p.= Substitution of 10th base of 3'UTR - no effect predicted No effect predicted OTX2_00011 3' UTR 880 CCTGTA G A AACCTC Substitution 3'UTR Direct Sequencing - - - Control None Ragge 2005 [15846561] , United Kingdom (Great Britain):Edinburgh DNA SEQ rs171978 in dbSNP. Published as 1050G/A: should be 1051G/A 1 - - - - Y - N - -
+/+ All - Whole gene deletion (120 kb) r.0 p.0 - - OTX2_00063 - - - - - - Deletion - CGH - - Heterozygous deletion of OTX2 gene Latypova 2016 Mandibular dysostosis [27378064], United Kingdom (Great Britain):Edinburgh DNA CGH Parental samples not available 1 - female - - - - - Mandibular dysostosis, micrognathia, agenesis of external auditory meatus. Hypermetropia, astigmatism and pigmented retinal lesions but no developmental ocular malformations -
+/+ All - Whole gene deletion (400 kb) r.0 p.0 - - OTX2_00054 - - - - - - Deletion - CGH - - Deletion of OTX2 gene Case 1 Patat 2013 Otocephaly-Dysgnathia Complex (24167467), United Kingdom (Great Britain):Edinburgh DNA SEQ Healthy parents do not have the deletion 1 - male Sporadic Sporadic - - - Child born at 30 weeks of gestation with agenesis of the mandible, microstomia, dysmorphic ears. Eyes normal on external inspection. Neonatal death. -
+/+ All - Whole gene deletion + insertion g.5600653158867091delins931 r.0 p.0 - - OTX2_00030 - - - - - - Insertion/Deletion - MLPA - - 1.9Mb deletion + 931b insertion Dateki 2010 Case 5 Anophthalmia / microphthalmia [19965921], United Kingdom (Great Britain):Edinburgh DNA SEQ Cryptic microdeletion detected by MLPA; confirmed by FISH. Delineated by CGH oligo array 1 94 Japanese patients male Sporadic Sporadic - - - Right microphthalmia; left anophthalmia; developmental delay; pituitary hypoplasia by MRI -
+/+ All - Whole gene deletion 14q22.2q23.1(54,287,767-56,543,234)x1 r.0 p.0 No transcription No translation OTX2_00049 - - - - - - Deletion - CGH - - Proband also has a paternal deletion of 4q43 Delahaye 2012 Patient 3 Microphthalmia syndrome [22234157] [24033328], United Kingdom (Great Britain):Edinburgh DNA CGH 8 family members share the same 2.3 Mb OTX2 deletion. Phenotypes range from unaffected to various combinations of colobomatous microphthalmia, palate anomalies, facial dysmorphism, renal malformation, microcephaly, and intellectual disability. Proband also has a deletion of 4q34 1 - male Familial Familial - - - Microphthalmia, intellectual disability -
+/+ All - Whole gene deletion 14q23.1q23.1(56,326,564-56,433,789)x1 r.0 p.0 - - OTX2_00050 - - - - - - Deletion - CGH - - Patient also has a deletion of 11p15 Delahaye 2012 Patient 4 Anophthalmia syndrome [22234157], United Kingdom (Great Britain):Edinburgh DNA CGH Proband also has a deletion of 11p15 1 - female - Sporadic - - - Severe bilateral microphthalmia, facial dysmorphism, developmental delay, growth hormone deficiency. Anterior pituitary hypoplasia and ectopic posterior pituitary gland by MRI. -
+/+ All - Whole gene deletion chr14(52,820,533-60,588,720)x1 r.0 p.0 - - OTX2_00051 - - - - - - Deletion - CGH - - - Chassaing 2013 Patient 19 Anophthalmia syndrome [24033328], United Kingdom (Great Britain):Edinburgh DNA CGH 7.7 Mb deletion detected by QMPSF, confirmed by aCGH. 1 - male - Sporadic - - - Pregnancy terminated at 33 weeks following detection bilateral anophthalmia and brain anomalies. Autopsy confirmed temporal cortical dysplasia and vermian neuronal heterotopia -
+/+ All - Whole gene deletion g.52830547- 59031284 r.0 p.0 - - OTX2_00043 - - - - - - Deletion - CGH - - Whole gene deletion (6.2 Mb) Takenouchi et al Anterior segment dysgenesis [23103883], United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 Japanese female - Sporadic - - - Anterior segment dysgenesis with severe microcornea; developmental delay; progressive white matter loss -
+/+ All - Whole gene deletion g.53758044-56834649 r.0 p.0 - - OTX2_00016 - - - - - - Deletion - FISH - - Whole gene deletion (3Mb) Wyatt 2008 Case 1 Severe microphthalmia Wyatt 2008 Case 1 [18781617], United Kingdom (Great Britain):Edinburgh DNA FISH Cryptic heterozygous 3Mb de novo deletion initially detected by FISH with BACs near OTX2, then characterised in detail by oligo array CGH 1 - female Sporadic Sporadic - - - Bilateral extreme microphthalmia; otherwise normal -
+/+ All - Whole gene deletion g.56094000-62594000 r.0 p.0 - - OTX2_00048 - - - - - - Deletion - CGH - - Whole gene deletion (6.5 Mb) Case ID 3000 Anophthalmia (24498598), United Kingdom (Great Britain):Edinburgh DNA SEQ - 1 German female - Sporadic - No - Bilateral anophthalmia, pituitary hypoplasia, developmental delay, sleep disturbance -
+/+ All - Whole gene deletion g.56224000-56679000 r.0 p.0 - - OTX2_00047 - - - - - - Deletion - CGH - - Whole gene deletion (455 kb) Case ID 3346 Anophthalmia (24498598), United Kingdom (Great Britain):Edinburgh DNA SEQ Neither parent has the deletion 1 Polish male Sporadic Sporadic - No - Bilateral anophthalmia -
+/+ All - Whole gene deletion g.56268037-57541514 r.0 p.0 - - OTX2_00017 - - - - - - Deletion - MLPA - - Whole gene deletion (1.28Mb) Wyatt 2008 Case 2 Anophthalmia Wyatt 2008 Case 2 [18781617], United Kingdom (Great Britain):Edinburgh DNA MLPA Cryptic heterozygous de novo deletion (1.3Mb) initially detected with an OTX2 exon 2 MLPA probe, then characterised by oligo array CGH 1 - female Sporadic Sporadic - - - Bilateral anophthalmia. Skull fracture, subdural haematoma; developmental delay -
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Legend: [ OTX2 full legend ]
Sequence variations are described basically as recommended by the Ad-Hoc Committee for Mutation Nomenclature (AHCMN), with the recently suggested additions (den Dunnen JT and Antonarakis SE [2000], Hum.Mut. 15:7-12); for a summary see Nomenclature. Coding DNA Reference Sequence, with the first base of the Met-codon counted as position 1.
Path.: Variant pathogenicity, in the format Reported/Concluded; '+' indicating the variant is pathogenic, '+?' probably pathogenic, '-' no known pathogenicity, '-?' probably no pathogenicity, '?' effect unknown. Exon: Exon numbering. Legacy DNA ID: Legacy DNA ID DNA change: Variation at DNA-level (see Full Legend for examples) RNA change: Variation at RNA-level (see Full Legend for examples) Protein change: Variation at protein level (see Full Legend for examples) RNA information: Additional information about RNA change Protein information: Additional information about protein change OTX2 DB-ID: Database IDentifier; When available, links to OMIM ID's are provided. Location: Variant location at DNA level. Base number: Location of DNA change 5' Sequence Context: 6 bases immediately 5' of the change Original Sequence: Original (normal) sequence Variant Sequence: Variant (new/mutated) sequence 3' Sequence Context: 6 bases immediately 3' of the change Type: Type of variant at DNA level. Domain: NTD, N-terminal domain; HD, homeodomain; CTD, C-terminal domain Detection Method: Mutation detection technique RE Site: Variant creates (+) or destroys (-) a restriction enzyme recognition site. Frequency: Frequency of variant Remarks: Other remarks about the sequence change Patient ID: Internal patient reference Disease: Disease phenotype, as reported in paper/by submitter, unless modified by the curator. Reference/Submitter: Links to PubMed ID (if available) and Submitter ID Template: Variant detected in DNA, RNA and/or Protein. Technique: Technique used to detect the variation. # Reported: Number of times this case has been reported Population: Patient population Gender: Patient gender Sequence Inheritance: Sequence Inheritance Phenotype Inheritance: Phenotype Inheritance Second PCR: Second PCR CIS: Other Mutation in Cis Conserved residue: Variation affects conserved base or amino acid Related Phenotype: Related Phenotype Unrelated Phenotype: Unrelated Phenotype