19p13 microduplications encompassing NFIX are responsible for intellectual disability, short stature and small head circumference

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of th...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2018-01, Vol.26 (1), p.85-93
Main Authors: Trimouille, Aurélien, Houcinat, Nada, Vuillaume, Marie-Laure, Fergelot, Patricia, Boucher, Cécile, Toutain, Jérôme, Caignec, Cédric Le, Vincent, Marie, Nizon, Mathilde, Andrieux, Joris, Vanlerberghe, Clémence, Delobel, Bruno, Duban, Bénédicte, Mansour, Sahar, Baple, Emma, McKeown, Colina, Poke, Gemma, Robertshaw, Kate, Fifield, Eve, Fabretto, Antonella, Pecile, Vanna, Gasparini, Paolo, Carrozzi, Marco, Lacombe, Didier, Arveiler, Benoît, Rooryck, Caroline, Moutton, Sébastien
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - genetics
Abnormalities, Multiple - pathology
Adolescent
Child
Child, Preschool
Chondrocytes
Chondrogenesis
Chromosome Duplication
Chromosomes, Human, Pair 19 - genetics
Copy number
Female
Genotype & phenotype
Humans
Infant
Intellectual disabilities
Intellectual Disability - genetics
Intellectual Disability - pathology
Macrocephaly
Male
Neurogenesis
NFI Transcription Factors - genetics
Nfix gene
Pathogenicity
Phenotypes
Syndrome
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Summary:Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-017-0037-7