Variants in nuclear factor I genes influence growth and development

Martin Zenker, Jens Bunt, Ina Schanze, Denny Schanze, Michael Piper, Manuela Priolo, Erica H. Gerkes, Richard M. Gronostajski, Linda J. Richards, Julie Vogt, Marja W. Wessels, Raoul C. Hennekam

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall–Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.

Original languageEnglish
Pages (from-to)611-626
Number of pages16
JournalAmerican Journal of Medical Genetics, Part C: Seminars in Medical Genetics
Volume181
Issue number4
DOIs
StatePublished - Dec 1 2019

Keywords

  • NFIA
  • NFIB
  • NFIX
  • intellectual disability
  • macrocephaly
  • nuclear factor one

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