Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities

Marcello Scala, Kamal Khan, Claire Beneteau, Rachel G. Fox, Sandra von Hardenberg, Ayaz Khan, Madeleine Joubert, Lorraine Fievet, Marie Musquer, Claudine Le Vaillant, Julie Korda Holsclaw, Derek Lim, Ann-Cathrine Berking, Andrea Accogli, Thea Giacomini, Lino Nobili, Pasquale Striano, Federico Zara, Annalaura Torella, Vincenzo NigroBenjamin Cogné, Max R. Salick, Ajamete Kaykas, Kevin Eggan, Valeria Capra, Stéphane Bézieau, Erica E. Davis*, Michael F. Wells*

*Corresponding author for this work

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    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 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing 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. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors 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.
    Original languageEnglish
    Article number101057
    Number of pages15
    JournalGenetics in Medicine
    Volume26
    Issue number4
    Early online date27 Dec 2023
    DOIs
    Publication statusPublished - Apr 2024

    Bibliographical note

    Funding:
    M.F.W. is supported by the NIMH/NIH (R00MH119327). E.E.D. is supported by funds from the NICHD/NIH (R01HD105868) and NIMH/NIH (R01MH106826). E.E.D. is the Ann Marie and Francis Klocke, MD Research Scholar. P.S., F.Z., and M.S. are supported by #NEXTGENERATIONEU (NGEU), the Ministry of University and Research, National Recovery and Resilience Plan, and project MNESYS (PE0000006)—A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). This work is also supported by the Italian Ministry of Health, RICERCA CORRENTE. The authors also acknowledge the Italian Ministry of Health (grant # RF-2016-02361949) to F.Z.

    Keywords

    • CACHD1
    • Human stem cell-derived neural
    • progenitors
    • Neurodevelopmental disorders
    • Voltage-gated calcium channels
    • Zebrafish

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