14q22.3 duplication including OTX2

14q22.3 duplication including OTX2 in a girl with medulloblastoma

The gene OTX2 is located on chromosome 14q22.3 and is essential for the normal developmental of the brain. Individuals with heterozygous loss of function of OTX2 through pathogenic variants in OTX2 or 14q22.3 deletions have been reported in patients with microphthalmia/anophthalmia, corpus callosum hypoplasia, pituitary hypoplasia, ear anomalies, short stature, seizure, developmental delay, and intellectual disability. Duplications of the 14q22.3 region are rarer and have been reported in patients with combined pituitary hormone deficiency, oculo-auriculo-vertebral spectrum, and hemifacial microsomia. A previous paper, Zielinski et. al, described five individuals in a family with hemifacial microsomia who carried a 1.3 Mb duplication of 14q22.3 including OTX2; one family member presented with medulloblastoma diagnosed at age of 7 years, suggesting a potential link between OTX2 germline duplication and medulloblastoma. Blake et. al. report another 6-year-old girl with an inherited 14q22.3 duplication including OTX2 who presented with developmental delay and medulloblastoma. The proband was diagnosed with nonmetastatic medulloblastoma at the age of 3 years, after being diagnosed with developmental delays in walking and talking and a 4-month period of progressive ataxia. In comparison to other affected individuals, she did not present with any dysmorphic features. She also has a dizygotic twin brother who is otherwise healthy and has not undergone genetic testing. The 14q22.3 duplication was inherited from the proband’s mother, who has a history of language delay and completed speech therapy as a child. A chromosomal microarray detected the 413 kb interstitial duplication in 14q22.3 that included the OTX2 gene in the proband and her mother. Exome sequencing also revealed a variant of uncertain significance in the gene SUFU, but it is unlikely to be contributory to patient’s medical history. More research is necessary to confirm the association between duplication of OTX2 and medulloblastoma development.

Blake et al. “14q22.3 duplication including OTX2 in a girl with medulloblastoma: A case report with literature review”. “American journal of medical genetics. Part A” 2024, v.194 (7), e63604.