PUBLICATION
Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities
- Authors
- Scala, M., Khan, K., Beneteau, C., Fox, R.G., von Hardenberg, S., Khan, A., Joubert, M., Fievet, L., Musquer, M., Le Vaillant, C., Holsclaw, J.K., Lim, D., Berking, A.C., Accogli, A., Giacomini, T., Nobili, L., Striano, P., Zara, F., Torella, A., Nigro, V., Cogné, B., Salick, M.R., Kaykas, A., Eggan, K., Capra, V., Bézieau, S., Davis, E.E., Wells, M.F.
- ID
- ZDB-PUB-240103-1
- Date
- 2023
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 26(4): 101057 (Journal)
- Registered Authors
- Davis, Erica
- Keywords
- CACHD1, facial abnormalities, human stem cell-derived neural progenitors, neurodevelopmental disorders, voltage-gated Calcium channels, zebrafish
- MeSH Terms
-
- Abnormalities, Multiple*/genetics
- Animals
- Craniofacial Abnormalities*/genetics
- Humans
- Intellectual Disability*/genetics
- Musculoskeletal Abnormalities*/genetics
- Neurodevelopmental Disorders*/genetics
- Phenotype
- Syndrome
- Zebrafish/genetics
- PubMed
- 38158856 Full text @ Genet. Med.
Citation
Scala, M., Khan, K., Beneteau, C., Fox, R.G., von Hardenberg, S., Khan, A., Joubert, M., Fievet, L., Musquer, M., Le Vaillant, C., Holsclaw, J.K., Lim, D., Berking, A.C., Accogli, A., Giacomini, T., Nobili, L., Striano, P., Zara, F., Torella, A., Nigro, V., Cogné, B., Salick, M.R., Kaykas, A., Eggan, K., Capra, V., Bézieau, S., Davis, E.E., Wells, M.F. (2023) Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities. Genetics in medicine : official journal of the American College of Medical Genetics. 26(4):101057.
Abstract
Purpose We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations.
Methods We performed phenotypic characterization of six participants from four unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing (ES) to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models, and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line.
Results Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. ES revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors (NPCs) revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in NPCs resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism.
Conclusion Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping