Corpus Callosum (CC) anomalies are midline congenital abnormalities, presenting as isolated malformations or associated with intra and extra-cranial findings, significantly affecting prognosis. Genetic causes or environmental factors can disrupt proper CC development during embryonic development.
Recognized genetic causes include chromosomal abnormalities, genomic rearrangements and single nucleotide/small indels mutations. However, in many cases molecular bases of CC abnormalities cannot be identified, given the different developmental processes and pathways that may be dysregulated.
Many different genes and transmission patterns have been described in non isolated forms , whereas the genetics of isolated forms remain poorly understood.
Prenatally detected CC anomalies often result in voluntary interruption of pregnancy, but data about postnatal outcome are insufficient.
Standard and molecular karyotype (arrayCGH or SNParray) should always be performed, followed by NGS (Next Generation Sequencing) approaches, as exome sequencing.
According to the results of a retrospective analysis of a cohort of 104 fetuses performed by our group in the last few years, the application of exome sequencing together with an accurate clinical and instrumental characterization is essential to reach a definitive diagnosis.
The aim of this project is the recruitment of additional cases affected by CC anomalies, expanding the pre-existing cohort, starting from prenatal period and plannig a follow-up in the postnatal period, performing in all cases exome sequencing. This approach could permit to better characterize the molecular bases of isolated and non-isolated forms of CC anomalies, improving genetic counseling and disclosing novel genotype-phenotype correlations both in prenatal and postnatal period.
This project can have impact on diagnosis and clinical management of CC anomalies, and in elucidating the molecular bases of these conditions.
This multidisciplinary project on CC abnormalities could have impact on both diagnosis and research of molecular bases of these genetic conditions.
In prenatal diagnosis, after US suspicion of a CC malformation, fetal MRI is routinely performed to confirm the diagnosis and can be repeated in the third trimester in order to rule out associated anomalies (i.e. neuronal migration disorders) which can become evident later in pregnancy. Furthermore, in apparently isolated forms in prenatal diagnosis, a high risk to detect additional anomalies after birth exists (D'Antonio et al., 2016).
This prognosis' uncertainty often results in voluntary interruption of pregnancy, although in literature homogeneous data are not available about the definite impact on neurodevelopmental outcome without a definite diagnosis.
In the past five years a retrospective analysis of 104 fetuses' prenatal data (imaging and genetics) affected by CC anomalies has been performed and published by our group (Manganaro et al., 2017). In some cases, selected from this cohort, the application of exome sequencing in prenatal or postnatal period has permitted to reach a definitive diagnosis and to describe new pathogenic variants in known disease genes, expanding the phenotypic spectrum and establishing recurrence risks (Bernardo et al., 2017, Traversa et al., 2019). In another postnatal case selected from the same cohort, a very complex molecular diagnosis of chromosomal and single gene disorder co-inheritance has been achieved and recently published (Traversa&Marchionni et al., 2020).
According to these results, in this project, we plan to expand the pre-existing cohort and to recruit new prenatal and postnatal cases affected by CC abnormalities. The molecular characterization of these cases by the routine application of exome sequencing together with an accurate clinical and imaging characterization, will improve genotype-phenotype correlations, genetic counseling and follow-up. Moreover, it can be a valuable approach in identifying new genes and pathways related to these conditions.