ClinVar Genomic variation as it relates to human health

Gait ataxia (present) , Spasticity (present) , Microcephaly (present) , Intellectual disability (present) , Growth delay (present) , Delayed speech and language development (present) , Short stature (present) , Cerebellar ataxia (present) , Delayed gross motor development (present) , Intellectual disability (present) (less)

In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay (MCOPS3; 206900), Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion at nucleotide 70 (70del20) of the SOX2 gene, resulting in a frameshift upstream of the HMG box and a premature termination signal 65 codons downstream. The authors noted that the deleted segment was flanked by the short GGCGGC repeat sequence, suggesting slipped-strand misrepairing as the origin of the deletion. In male monozygotic twins with ocular defects, esophageal atresia, and genital abnormalities, Zenteno et al. (2006) identified heterozygosity for the 70del20 mutation in the SOX2 gene. Both infants had tracheoesophageal fistula, but otherwise exhibited a discordant phenotype: 1 twin had left clinical anophthalmia and bilateral cryptorchidism, whereas the other had normal globes, narrowing of the right palpebral fissure, and no genital abnormalities. The authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect and the first example of monozygotic twins discordant for anophthalmia. In a 22-year-old female with left clinical anophthalmia and right microphthalmia, learning difficulties, and primary amenorrhea, Kelberman et al. (2006) identified heterozygosity for a de novo 70del20 mutation in the SOX2 gene. Brain MRI revealed an abnormal hypoplastic pituitary gland in a small sella turcica with an absent left eye and optic nerve. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation. Kelberman et al. (2008) identified this deletion (70_89del) in a 14.5-year-old girl who presented with bilateral anophthalmia at birth. Brain MRI showed an arachnoid cyst in the suprasellar area, with right deflection of the pituitary pedunculus. She later developed gonadotropin deficiency with low basal gonadotropin concentrations and poor response to gonadotropin-releasing hormone (GNRH; 152760) stimulation. There was no evidence of learning difficulties. In a girl and 2 boys with bilateral clinical anophthalmia or severe microphthalmia, Schneider et al. (2009) identified the 70del20 mutation in the SOX2 gene. All 3 patients had developmental delay. Neuroimaging showed a hamartoma of the tuber cinereum in the 2-year-old girl, but was normal in the other 2 patients; none had pituitary anomalies. The 2 boys displayed genital anomalies, including micropenis, cryptorchidism, and foreskin adhesion. Other features seen in the 2 boys included a heart murmur in 1 patient and 2-3 toe syndactyly, febrile seizures, and mild pectus excavatum in the other. The girl had a half-sister with unilateral clinical anophthalmia and mental retardation. (less)