TY - JOUR
T1 - Variants in nuclear factor I genes influence growth and development
AU - Zenker, Martin
AU - Bunt, Jens
AU - Schanze, Ina
AU - Schanze, Denny
AU - Piper, Michael
AU - Priolo, Manuela
AU - Gerkes, Erica H.
AU - Gronostajski, Richard M.
AU - Richards, Linda J.
AU - Vogt, Julie
AU - Wessels, Marja W.
AU - Hennekam, Raoul C.
N1 - Funding Information:
German Ministry of Education and Research (BMBF), Grant/Award Number: GeNeRARe 01GM1519A; National Health and Medical Research Council, Grant/Award Numbers: GNT1100443, GNT1120615 Funding information
Funding Information:
We thank Dr Jan Liebelt (Adelaide, South Australia, Australia) and Dr Aurélien Trimouille (Bordeaux, France) for allowing us to publish clinical pictures of their patients. We are grateful to Rowan Tweedale for her critical comments on the manuscript. This work was financially supported by the National Health and Medical Research Council, Australia, Grant/Award Number: GNT1100443 and GNT1120615; and the German Ministry of Education and Research (BMBF), Grant/Award Number: GeNeRARe 01GM1519A. RCH co‐authors this manuscript as member of the European Reference Network ITHACA.
Funding Information:
We thank Dr Jan Liebelt (Adelaide, South Australia, Australia) and Dr Aurélien Trimouille (Bordeaux, France) for allowing us to publish clinical pictures of their patients. We are grateful to Rowan Tweedale for her critical comments on the manuscript. This work was financially supported by the National Health and Medical Research Council, Australia, Grant/Award Number: GNT1100443 and GNT1120615; and the German Ministry of Education and Research (BMBF), Grant/Award Number: GeNeRARe 01GM1519A. RCH co-authors this manuscript as member of the European Reference Network ITHACA.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - NFIA
KW - NFIB
KW - NFIX
KW - intellectual disability
KW - macrocephaly
KW - nuclear factor one
UR - http://www.scopus.com/inward/record.url?scp=85075126623&partnerID=8YFLogxK
U2 - 10.1002/ajmg.c.31747
DO - 10.1002/ajmg.c.31747
M3 - Article
C2 - 31730271
AN - SCOPUS:85075126623
SN - 1552-4868
VL - 181
SP - 611
EP - 626
JO - American Journal of Medical Genetics, Part C: Seminars in Medical Genetics
JF - American Journal of Medical Genetics, Part C: Seminars in Medical Genetics
IS - 4
ER -