Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes

Filomena Pirozzi, Benson Lee, Nicole Horsley, Deepika D. Burkardt, William B. Dobyns, John M. Graham, Maria L. Dentici, Claudia Cesario, Jens Schallner, Joseph Porrmann, Nataliya Di Donato, Pedro A. Sanchez-Lara, Ghayda M. Mirzaa

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.

Original languageEnglish (US)
Pages (from-to)2719-2738
Number of pages20
JournalAmerican Journal of Medical Genetics, Part A
Volume185
Issue number9
Early online dateJun 4 2021
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
We thank the patients, their families and care providers for their contribution to this study. We thank Dr. M. Elizabeth Ross, Professor of Neurology and Neuroscience, and the Ross Laboratory at Weill Cornell Medicine for their expert input regarding the function and role of CCND2 in brain development. We also thank Dr. Daniel Doherty, Professor of Pediatrics and Developmental Medicine, for providing the control fibroblast cell line used in this manuscript (UW402‐4). Research reported in this publication was supported by Jordan's Guardian Angels and the Sunderland Foundation (to Filomena Pirozzi and Ghayda M. Mirzaa), and the Brotman‐Baty Institute (to Ghayda M. Mirzaa); Nataliya Di Donato work was supported by German Research Foundation (DI 2170/3‐1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication.

Funding Information:
We thank the patients, their families and care providers for their contribution to this study. We thank Dr. M. Elizabeth Ross, Professor of Neurology and Neuroscience, and the Ross Laboratory at Weill Cornell Medicine for their expert input regarding the function and role of CCND2 in brain development. We also thank Dr. Daniel Doherty, Professor of Pediatrics and Developmental Medicine, for providing the control fibroblast cell line used in this manuscript (UW402-4). Research reported in this publication was supported by Jordan's Guardian Angels and the Sunderland Foundation (to Filomena Pirozzi and Ghayda M. Mirzaa), and the Brotman-Baty Institute (to Ghayda M. Mirzaa); Nataliya Di Donato work was supported by German Research Foundation (DI 2170/3-1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication.

Funding Information:
Brotman‐Baty Institute; German Research Foundation, Grant/Award Number: DI 2170/3‐1; Jordan's Guardian Angels; Sunderland Foundation Funding information

Publisher Copyright:
© 2021 Wiley Periodicals LLC.

Keywords

  • cyclin D2
  • inverse phenotypes
  • megalencephaly
  • megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH syndrome)
  • microcephaly

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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