Published on 21.05.2021
From research on the Pierre Robin sequence to the discovery of a genetic cause of intellectual disability
The story begins 18 years ago with a young patient hospitalized for a Pierre Robin sequence, a pathology characterized by a malformation of the face associating a small backward chin and a cleft palate leading to eating and breathing difficulties in the newborn. The patient also suffers from epilepsy, delayed motor development, and intellectual disability. This patient has been followed in Pediatrics at Hôpital Necker-Enfants Malades AP-HP since her birth via the SPRATON reference center.
The Embryology and Genetics of Malformations research laboratory, directed by Prof. Jeanne Amiel at Imagine, performed exome sequencing of the patient and her two parents and identified a de novo variant in the ANKRD17 gene not yet described in human pathology. Thanks to international collaborations based on the sharing of genomic data, a cohort of 34 patients was built in a few months.
Variants in this gene result in consistent but variable severity of developmental delay/intellectual disability, particularly affecting language. Other signs are inconsistent and include growth retardation, feeding difficulties, nonspecific brain MRI abnormalities, epilepsy and/or abnormal EEG, susceptibility to recurrent infections, ophthalmologic abnormalities, gait/balance disorders, joint hypermobility, and nonspecific morphologic features.
While we were looking for a genetic cause for the Pierre Robin sequence associated with other symptoms such as epilepsy, we identified a rare monogenic form of intellectual disability. This is the common denominator for all these patients and the Pierre Robin sequence is rare, found in 2 of the 34 patients reported. This mutation appears de novo, i.e. it is specific to the child and neither of the parents carries it
Intellectual disability, very heterogeneous genetic causes
Rare and heterogeneous, this is what characterizes the monogenic genetic causes of intellectual disability (ID). A real public health issue, affecting 1 to 2% of the population, ID presents itself in an isolated or syndromic manner associating clinical, radiological or biological signs that are more or less discriminating.
"Today, there are more than 500 monogenic causes of isolated or syndromic intellectual disability. Each genetic variant is rare. For example, the FMR1 gene mutation that causes Fragile X syndrome, the leading cause of hereditary intellectual disability, explains only 1% of cases of ID. Here, with the ANKRD17 gene, we are more like 1 per 1000," explains Christopher Gordon, author of the study. "This is a group of genes whose function is not always linked to the development of the central nervous system, which has complicated the diagnosis".
A further step towards diagnosis
Diagnosis, naming the cause of a disease or disorder, is an essential step for patients and their families, but also to better understand the disease and hopefully one day treat it. The study showed that loss-of-function mutations in this gene are responsible for ID in humans. This publication will save considerable time in the diagnosis of this form of intellectual disability if a de novo mutation is identified in a patient.
This discovery could also stimulate further research on the role of this particular gene and this family of genes in general during brain development in other specialized teams. The team of Dr. Maya Chopra, currently practicing in the Rosamund Stone Zander Translational Neuroscience Center at Boston Children's Hospital / Harvard Medical School, who co-lead this study during a two-year stint at Imagine, will continue clinical and basic research by studying new patients and establishing models using patient IPS cells.
This is a first step and it is the whole approach of Institut Imagine that is illustrated here. We start with the patient, in this case a young girl who has been followed since birth at Hôpital Necker-Enfants malades AP-HP. We identify new genes that generate research work that accelerates diagnosis for other patients and improves genetic counseling and care