Table 1.
Summary of OTX2 mutations in human patients reported to date. The reference sequence NM_172337.1 was used.
| Reference | Nucleotide Mutation* |
Amino Acid Mutation |
Eye Anomalies | Other Structural Brain Anomaly |
Abnormal Pituitary Structure/ Function |
SS | DD/ MR |
Other features | Family history | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AN | MI | ONH/A | ASD | Other | |||||||||
| Ragge et al. (7) | c.81delC | p.S28PfsX23 | - | B | B | - | - | U | U | U | - | - | Unaffected mother mosaic; affected sibling |
| Ragge et al. (7) | c.81delC | p.S28PfsX23 | - | B | U | - | - | Y | U | U | U | Pregnancy terminated | Sibling of above |
| Wyatt et al. 2008 | c.93C>G | p.Y31X | - | L | U | - | R | U | U | U | U | U | Parents DNA normal |
| Wyatt et al. 2008 | c.106dupC | p.R36PfsX52 | - | R | U | - | - | U | U | - | - | - | Affected sibling (below), Parents DNA normal; Presumed mosaicism |
| Wyatt et al. 2008 | c.106dupC | p.R36PfsX52 | R | - | U | - | L | U | U | - | - | - | Brother of above |
| Ragge et al. (7) | c.117_118delCC | p.R40GfsX47 | B | - | B | - | - | Y | NS | Y | - | - | Unaffected mother carries mutation |
| Ragge et al. (7) | c.117_118delCC | p.R40GfsX47 | - | - | - | - | - | U | U | - | - | - | Mother of above |
| Patient 1A, this study | c.136dupA | p.T46NfsX42 | - | B | B | - | - | - | NS | - | - | Microcephaly, anteriorly placed anus, sacral dimple | Affected father carries mutation |
| Patient 1B, this study | c.136dupA | p.T46NfsX42 | - | L | L | L | B | U | U | - | - | - | Father of above |
| Dateki et al. 2010 | c.214_217delGCACinsCA | p.A72HfsX15 | - | B | U | U | U | U | - | - | U | - | Parents' DNA normal |
| Dateki et al. 2010 | c.221_236del | p.K74SfsX30 | R | L | U | U | U | - | Y | Y | Y | Retractile testis | Parents' DNA normal |
| Ragge et al. 2005 | c.265C>G | p.R89G | - | B | B | - | B | - | NS | - | - | - | Mother had previous stillbirth; Parents' DNA normal |
| Wyatt et al. 2008 | c.289C>T | p.Q97X | - | B | U | - | - | U | U | U | U | U | Dizygotic twin and father with mutation |
| Wyatt et al. 2008 | c.289C>T | p.Q97X | - | - | U | - | B | U | U | U | U | U | Twin of above |
| Wyatt et al. 2008 | c.289C>T | p.Q97X | U | U | U | U | 1 | U | U | U | U | 'Reduced vision" one eye | Father of above |
| Ragge et al. (7) | c.295C>T | p.Q99X | B | - | B | - | - | Y | U | U | Y | Seizures | Unaffected father carries mutation |
| Ragge et al. (7) | c.295C>T | p.Q99X | - | - | - | - | - | U | U | - | - | - | Father of above |
| Patient 2, this study | c.313C>T | p.Q105X | B | - | B | - | - | - | NS | - | Y | Wolf-Parkinson White syndrome, feeding difficulties | Parents' DNA normal |
| Wyatt et al. (8) | c.371_372delAG | p.S125Wf sX11 | B | - | U | - | - | U | U | U | Y | U | Unaffected mother carries mutation |
| Wyatt et al. (8) | c.371_372delAG | p.S125Wf sX11 | - | - | - | - | - | U | U | - | - | - | Mother of above |
| Dateki et al. (11) | c.402_403insC | p.S135LfsX2 | B | - | B | - | - | - | Y | Y | Y | Cleft palate | Parents' DNA normal |
| Tajima et al. 2009 | c.405_406insCT | p.S136LfsX43 | B | - | B | - | - | Y | Y | Y | Y | Microcephaly, small penis, cryptorchidism | Parents' DNA normal |
| Henderson et al. (10) | c.413C>G | p.S138X | - | - | - | - | B | - | Y | Y | U | Feeding difficulties | Parents' DNA normal |
| Patient 3, this study | c.456_457delGAinsAT | p.W152X | R | L | B | - | - | - | Y | Y | Y | Microcephaly, feeding difficulties | Parents' DNA normal |
| Ragge et al. (7) | c.464_465dup | p.S156LfsX23 | R | L | B | - | L | Y | NS | - | Y | Microcephaly | Parents' DNA normal |
| Ragge et al. 2005 | c.537T>A | p.Y179X | - | B | U | B | B | U | U | Y | Y | Seizures | Mother mosaic with pigmentary retinopathy; Affected brother and niece |
| Ragge et al. 2005 | c.537T>A | p.Y179X | - | B | - | B | B | - | NS | Y | Y | - | Brother of above, affected daughter (below) |
| Henderson et al. 2007 | c.537T>A | p.Y179X | - | R | U | B | B | Y | U | U | Y | Microcephaly, NF type 1; Mutations in PAX6 and NF1 | Daughter of above; mother with NF1 and PAX6 mutations |
| Patient 4, this study | c.553_556dupTATA | p.S186IfsX2 | - | B | B | - | R | - | Y | Y | Y | Microcephaly, hypotonia, hypoplastic labia minora | Parents' DNA normal |
| Dateki et al. 2010 | c.562G>T | p.G188X | - | B | U | U | U | - | Y | Y | Y | - | Parental testing not reported |
| Dateki et al. 2010 | c.562G>T | p.G188X | - | B | U | U | U | U | - | - | Y | Seizures | Unrelated to above; Parental testing not reported |
| Diaczok et al. 2008 | c.674A>G | p.N225S | U | U | - | U | U | - | Y | U | U | Feeding difficulties | Parental testing not reported |
| Diaczok et al. 2008 | c.674A>G | p.N225S | U | U | - | U | U | - | Y | U | U | Seizures, respiratory distress | Parental testing not reported |
| Dateki et al. 2010 | 2.86 Mb deletion incl OTX2 | whole gene deletion | L | R | U | U | U | - | Y | Y | Y | - | Parents' DNA normal |
| Wyatt et al. 2008 | 3.07 Mb deletion incl. OTX2 | whole gene deletion | - | B | - | - | - | - | NS | - | - | - | Parents' DNA normal |
| Wyatt et al. 2008 | 1.28 Mb deletion incl. OTX2 | whole gene deletion | B | - | U | - | - | U | U | U | Y | Skull fractures, Feeding difficulties | Parents' DNA normal |
| Nolen et al. (9) | 9.66 Mb deletion incl. OTX2 | whole gene deletion | B | - | B | - | - | Y | Y | Y | Y | Microcephaly, hypotonia, MCA | Parents' DNA normal |
AN=anophthalmia, MI=microphthalmia, ONH/A=optic nerve hypoplasia/aplaisa, ASD=anterior segment dysgenesis, SS=short stature, DD/MR=developmental delay/mental retardation, B=bilateral, R=right eye only, L=left eye only, U=unknown/not reported, 1=one eye affected, Y=yes, - = feature not present, NS=normal structure (pituitary), MCA=multiple congenital anomalies
Other' eye anomalies include cataract, coloboma, retinal anomalies, nystagmus, retinal dystrophy, posterior vitreous opacities, persistent pupillary membrane,
Mutations were numbered based upon OTX2 cDNA sequence NM_172337.1 transcript variant 2, which is the canonical sequence according to UniProt (http://www.uniprot.org/), with +1 as the A of the ATG start site to allow direct comparison;
Two mutations reported by Ragge et al. 2005, p.P133T and p.P134A, were excluded from this table due to their later assertion in Wyatt et al. 2008 (8) that these mutations were unlikely to be pathogenic. Two mutations reported by Dateki et al. 2010, p.T178S and p.A245V, were also excluded due to the authors assertion that they were likely to be rare polymorphisms (15).