Could a mutation in the TGIF-1 gene result in phenotypical expressions like pachygyria, intracerebral calcification, and neonatal epilepsy?

Mutations of the TGIF-1 gene in humans may be seen in connection with various complex malformation syndromes. Phenotypical expression may include microcephaly, hypotelorism, a single large incisor, clefts of lip and palate, and structural abnormalities of the brain (holoprosencephaly, corpus callosum malformation). Carriers of the mutation without physical signs have been described.

Our patient is a now 5-year-old girl. She started having bilateral tonic clonic seizures at the first day of life. Cerebral MRI showed calcifications in the ependyma of both lateral ventricles, pachygyria and hypoplasia of corpus callosum. Phenotypical signs include microcephaly and hypotelorism. Genetic studies showed a frameshift mutation in one copy of the TGIF-1 gene, which results in a premature termination of protein synthesis (heterozygous mutation c.246deIT,pPro83Leufs*51).

The identical mutation was detected in one copy of the TGIF-1 gene in her younger brother and both parents. The younger brother has a language delay and few morphological signs (hypotelorism, mid-face hypoplasia). Both parents have neither phenotypical nor clinical signs.

A further son was born 6 month ago. Prenatal ultrasound scan showed intracranial calcification and microcephaly. He started having tonic, clonic, and tonic clonic seizures on day one of life. His facial morphological abnormalities include mid-face hypoplasia, a broad nasal bridge, and low set ears. He has cerebral palsy. His cerebral MRI exhibits calcifications in both thalami-pachygyria and hypoplasia of corpus callosum. Genetic studies of this boy were declined by the parents.

It remains to be discussed whether this mutation of the TGIF-1 gene is connected with the occurrence of neonatal epilepsy and phenotypical signs and cerebral abnormalities like calcifications and pachygyria in two members of this family. Current literature is not coherent about the relevance of this mutation, and two family members are carriers without any physical signs.