CCDC149: a novel gene associated with hypopituitarism and neurodevelopmental impairment.

Two homozygous frameshifts in CCDC149, whose orthologue is expressed in the basal bodies of ciliated neurons in C. elegans, point to impaired ciliary function during hypothalamo-pituitary development.

Congenital hypopituitarism is a complex developmental disorder characterised by variable pituitary dysfunction, often associated with midline structural abnormalities affecting the brain, eyes and face, and only 10-15% of patients currently have an identified molecular basis. Next-generation sequencing in a subset of patients without known genetic aetiology identified two novel homozygous frameshifts in CCDC149, p.Gly278Ter and p.Leu222Ter, in two unrelated pedigrees comprising three patients. Phenotypes included growth hormone deficiency, hypogonadotropic hypogonadism and developmental delay or autism, with severe scoliosis in one pedigree and a small anterior pituitary on MRI in the other. In human embryonic brain tissue sections, CCDC149 localised to the developing hypothalamo-pituitary region at Carnegie stages 16-23, and CRISPR-Cas9-generated Ccdc149-null mice recapitulated patient phenotypes, including growth impairment and reduced fertility compared with wild-type littermates.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The strong argument is the convergence between expression in the developing hypothalamo-pituitary region and a null mouse model reproducing growth impairment and reduced fertility: this is not merely a candidate gene from a bioinformatic filter. Still, three patients in two families are not enough to establish gene-disease validity, and the pituitary phenotype of the mouse is not documented hormonally in what is reported. The ciliary hypothesis, supported by the C. elegans orthologue, is coherent but indirect: it needs confirmation before being used as an interpretive argument for a homozygous CCDC149 variant on an exome.

Analysis by Dr Thibaut Benquey