Table 1. Summary of PITX2 mutations and phenotypes identified in this study.
| Case | Mutationa/deletion | Predicted effect | Eye | Dental | Umbilicus | Heart | Hearing | Other | Age (years) | Family hx |
|---|---|---|---|---|---|---|---|---|---|---|
| Intragenic PITX2 mutations | ||||||||||
| 1 | c.134dupA | p.H45Qfs*154 | ARS, microcornea | MD, DA | RU, UH | − | − | Ankyloglossia | 1.5 | Yes |
| 2A | c.143_144delGC | p.S48Tfs*150 | ARS | HD | RU | − | − | 30 | Yes | |
| 2B | c.143_144delGC | p.S48Tfs*150 | ARS | HD | RU | − | − | DD, hypertelorism, prominent forehead | 2..5 | Child of 2A |
| 2C | c.143_144delGC | p.S48Tfs*150 | ARS | Unk | Omphalocele | − | Hearing loss | − | <1 | Child of 2A |
| 3 | c.185G>A | p.R62H | ARS | HD | UH | − | − | − | 40 | Yes |
| 4A | c.225G>A | p.W75* | ARS, GL, vascular loops | HD | RU | − | − | Hypospadias | 37 | Yes |
| 4B | c.225G>A | p.W75* | ARS | Unk | RU, UH | − | − | MH, small mouth, hair whorl ankyloglossia, sacral dimple, | <1 | Child of 4A |
| 5 | c.225G>A | p.W75* | ARS, aniso-metropia | HD, MD | RU | − | − | MH, Imperforate anus, thin upper lip | 13 | Yes |
| 6 | p.247G>T | p.V83F | ARS | HD | RU | − | − | Mild DD, GD, abnormal head size | 3 | No |
| 7 | c.253-11A>G | Truncated HD due to splicing defectb | ARS | HD, MD | RU | − | − | MH, small mouth, high arched palate, hyperextensible joints; clinodactyly; narrow nails, lopped ears, prominent occiput | 9 | No |
| 8 | c.253-11A>G | Truncated HD due to splicing defectb | Strabismus, amblyopia | HD | RU | Anomalous pulmonary venous return | − | DD, GD | 10 | No |
| 9 | c.253-11A>G | Truncated HD due to splicing defectb | PA, nystagmus, esotropia | − | UH | − | − | GD, nasal bridge anomaly, high arched palate, prognathia, smooth philtrum, long thin face, posteriorly rotated ears, microcephaly | 14 | No |
| 10 | c.253-1G>A | Truncated HD due to splicing defect | ARS | HD, delayed eruption | UH | − | − | Hypertelorism, Meckel's diverticulum | 2 | No |
| 11 | c.253-1G>A | Truncated HD due to splicing defect | ARS, myopia | HD, MD | RU | − | − | MH, microcephaly, thin upper lip, short philtrum, mild DD, asymmetric ocular position | 16 | No |
| 12 | c.257G>C | p.W86S | ARS | DA | UA | − | − | − | 43 | Yes |
| 13 | c.258G>T | p.W86C | ARS, microcornea | HD, MD | RU | − | − | MH, prognathia, Meckel's diverticulum | 3 | No |
| 14 | c.269G>C | p.R90P | ARS, GL | HD | UH | − | − | Prognathia, Meckel's diverticulum, broad forehead | 32 | No |
| 15 | c.289_290delAG | p.R97Gfs*101 | PA | Unk | RU | − | − | − | <1 | No |
| 16 | c.366delC | p.D122Efs*33 | ARS, GL | HD, persistent primary teeth | − | − | − | MH | 29 | Yes |
| 17 | c.398G>A | p.W133* | ARS, CA, CGL, PA nystagmus | HD | RU | − | − | Inguinal hernia | 1.5 | Yes |
| 18 | c.708_730del | p.S237Afs*48 | ARS | Unk | RU, UH | − | − | Small mouth, nasal bridge anomaly, anteriorly placed anus | <1 | No |
| PITX2 deletions | ||||||||||
| 19 | 4q25-q26 deletion (6.4 Mb) | Deletion of PITX2 ENPEP, C4orf32, C4orf16, TIFA, ALPK1, NEUROG2, LOC91431, C4orf21, LARP7, ANK2, CAMK2D, ARSJ, UGT8, AND NDST4 | ARS, GL | HD, MD | RU | − | − | MH, nasal bridge anomaly, low thyroid | 21 | No |
| 20 | 4q25 deletion (1.1 Mb) | Deletion of PITX2 EGF, ELOVL6, ENPEP | ARS, myopia (−12; −8), missing eye muscles (L), astigmatism | HD, persistent primary teeth | RU, UH | − | − | Micrognathia, abnormal ocular position, inguinal hernia, ulcerative colitis, diverticulitis, attention deficit hyperactivity disorder, micropenis, sleep disorder, transient ischemic attack, hypercholesterolinemia | 54 | Uncertain |
| 21 | 4q25-q28.2 deletion (19.2 Mb) | Deletion of PITX2 and 65 genes from ELOVL6 to SCLT1 | ARS, CGL, CA, severe IH/aniridia, | Natal tooth | RU | Ventricular septal defect | Hearing loss | Mild DD, MH, thin upper lip, high arched palate, low-set ears | <1 | No |
| 22 | Gene deletion (extent ND) | Deletion of PITX2 Other genes ND | ARS | HD, MD | Omphalocele | − | − | MH, Ridged palate | 3 | No |
| 23 | Gene deletion (extent ND) | Deletion of PITX2 Other genes ND | ARS, GL, retinal detachment | DA | − | − | − | − | 65 | Yes |
| 24 | Distant upstream region deletion (extent ND) | Deletion of regulatory region of PITX2 Other genes ND | ARS, blue sclerae | MD | UH, RU | − | − | Low hair line, DD, autism, digit anomaly, thin upper lip | 2 | No |
Abbreviations: ARS, Axenfeld-Rieger syndrome (any combination of posterior embryotoxon, irido-corneal adhesions, iris hypoplasia, and pupillary anomalies); CA, cataract; CGL, congenital glaucoma; DA, dental anomaly; DD, developmental delay; GD, growth disorder (short stature, failure to thrive); GL, glaucoma; HD, hypodontia; IH, iris hypoplasia; MD, microdontia; MH, maxillary hypoplasia; PA, Peters anomaly; RU, redundant umbilical skin; UA, umbilical anomaly; UH, umbilical hernia; Unk, unknown.
a
Numbering is relative to reference sequence NM_153427.1, where +1 is the A of the ATG initiation codon; novel mutations are shown in bold.
b
Confirmed by analysis presented by Maciolek et al.14