(1) Genetics Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal.
(2) Neurology Department, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.
(3) East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
(4) Department of Health, Genomics England, Queen Mary University of London, Charterhouse Square, London, UK.
(5) Neuroradiology Department, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.
(6) Research Data Analysis, CENTOGENE AG, Rostock, Germany.
(7) Laboratório de Imunologia Básica, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
- Clin Genet. 2021 Apr;99(4):588-593.
Congenital cranial dysinnervation disorders (CCDDs) are a heterogeneous group of neurodevelopmental phenotypes caused by a primary disturbance of innervation due to deficient, absent, or misguided cranial nerves. Although some CCDDs genes are known, several clinical phenotypes and their aetiologies remain to be elucidated. We describe a 12-year-old boy with hypotonia, developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. He had a long expressionless face, severe oromotor dysfunction, bilateral agenesis/severe hypoplasia of the VIII nerve with marked atresia of the internal auditory canals and cochlear labyrinth malformation. Trio-exome sequencing identified a homozygous loss of function variant in the NEUROG1 gene (NM_006161.2: c.202G > T, p.Glu68*). NEUROG1 is considered a causal candidate for CCDDs based on (i) the previous report of a patient with a homozygous gene deletion and developmental delay, deafness due to absent bilateral VIII nerves, and severe oromotor dysfunction; (ii) a second patient with a homozygous NEUROG1 missense variant and corneal opacity, absent corneal reflex and intellectual disability; and (iii) the knockout mouse model phenotype which highly resembles the disorder observed in humans. Our findings support the growing compelling evidence that loss of NEUROG1 leads to a very distinctive disorder of cranial nerves development.