Research project - Using CAD genomic data to improve the diagnosis of patients with microcephaly

Brain development is tightly regulated by numerous genes from conception through adolescence. Genetic or environmental anomalies can disrupt this developmental program and lead to reduced or excessive brain growth (microcephaly or macrocephaly), which may result in intellectual disability and epilepsy. Microcephaly can be diagnosed before birth (primary microcephaly, affecting 2 to 3% of newborns and caused by genetic or environmental factors) or after birth (secondary microcephaly).

The suspected genetic origin of primary microcephaly is often difficult to confirm, even after extensive testing. This creates challenges for families left without a diagnosis for their child, and for medical teams who are unable to provide clear prognostic information or genetic counseling.

This low diagnostic yield is due to both the clinical diversity of these conditions (isolated microcephalies or those associated with short stature or other malformations) and the likelihood that a different, less conventional genetic approach is needed than what is currently offered to families. The MICROC project, led by a consortium of pediatric neurologists, molecular biologists (both serving as clinical leads for the microcephaly indication in the PFMG2025), and researchers (mathematicians and neurobiologists) from NeuroDiderot (Inserm and Université Paris Cité), proposes to use innovative bioinformatic and mathematical methods—such as the search for novel types of variants or abnormal pathogenic variant burdens in patients—to reanalyze genomic data generated through the PFMG2025 and identify new genetic causes of primary microcephaly.