Table 1.
Summary of Neurologic and Urogenital Phenotypes
| - | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | 15 years | 15 years | 5.5 years | 12 weeks gestation | 3 years | 6 years | 7 years | 45 years | 2 years | 2 years | 12 years | 3 years |
| Brain malformation | MIHV HPE | semilobar HPE | agenesis of the corpus callosum | acrania, anencephaly | head CT unremarkable | dysgenesis of the corpus callosum, absent septum pellucidum, Chiari malformation, cortical dysplasia/polymicrogyria, and grey matter heterotopia | leukomalacia | not evaluated | not evaluated | brain MRI unremarkable | brain MRI unremarkable | not evaluated |
| Genitourinary malformation | not evaluated | not evaluated | renal asymmetry | not described on autopsy | micropenis, chordee, scrotal hypospadias, bilateral cryptorchidism, and uterus | glandular hypospadias and chordee | hypospadias, cryptorchidism, uterus and ovaries | uterine didelphys and streak gonads | clitoral hypertrophy, UGS, posterior fusion of the labia majora | grade 2 hypospadias, cryptorchidism, removal of right inguinal hernia identified as a fallopian tube, and uterus | streak gonads with rudimentary fallopian tubes, and UGS | clitoris, posterior labial fusion, labial rugation and pigmentation, uterus, fallopian tubes and ovaries |
| Head and facial features | macrocephaly, hypertelorism | microcephaly, epicanthal folds, long philtrum | not described | hypertelorism, flattened facial profile, absent nasal bone | not described | short upslanting palpebral fissures, low-set ears, and micrognathia | long face, large protruding ears, ptosis, small pointed nose | not described | not described | not described | not described | deformed pinnae, epicanthus inversus |
| Other | Developmental delay | developmental delay, syndactyly | ADHD, kyphoscoliosis, stiff joints, decreased subcutaneous fat | omphalocele | absent | developmental delay, strabismus, astigmatism, hyperopia, and alternating esotropia | developmental delay, bilateral rod and cone dysfunction, decreased vision, and latent nystagmus | absent | absent | developmental delay | developmental delay | developmental delay, strabismus, right esotropia |
| Genotypic sex | 46,XX | 46,XX | 46,XY | 46,XX | 46,XY | 46,XY | 46,XY | 46,XY | 46,XY | 46,XY | 46,XY | 46,XY |
| Phenotypic sex | female | female | male | female | male | male | male | female | female | male | female | female |
| Inheritance | de novo | unknown | de novo | de novo | de novo | de novo | unknown | unknown | de novo | de novo | de novo | de novo |
| Variant | c.2033_2034delCT (p.Ser678∗) | c.1415C>G (p.Ser472∗) | c.793-1G>A | c.223_224delAC (p.Thr75Cysfs∗8) | c.2739_2740delCT (p.Leu914Argfs∗14) | c.1510C>T (p.Arg504∗) | c.2573G>A (p.Trp858∗) | c.2073dupA (p.Ser692Ilefs∗2) | c.2698C>T (p.Arg900∗) | c.960dupA (p.Glu321Argfs∗6) | c.1189delA (p.Thr397Hisfs∗42) | c.681dupT (p.Lys228∗) |
Individuals 1–4 share the neurological phenotype, individuals 3 and 5–12 share diverse urogenital malformations, and individuals 3, 6, and 7 share an overlap of both. Notable discordance in genotypic and phenotypic sex is seen between the 46,XX and 46,XY individuals, but the significance requires further investigation. Transcript NM_002480.3 was used for all described variants in PPP1R12A. Abbreviations: MIHV—middle interhemispheric variant, HPE—holoprosencephaly, ADHD—attention deficit hyperactivity disorder, and UGS—urogenital sinus.