Abstract
Background
Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized
by delayed motor and/or cognitive milestones and by a variable range of intellectual
disability with or without an autistic behavior. Several genetic factors have been
implicated in intellectual disability onset and exome sequencing studies have recently
identified new inherited or de novo mutations in patients with neurodevelopmental disorders.
Case
We report the case of two monozygotic twins who came for the first time to our attention
at the age of 20 months for a global neurodevelopmental delay associated with an autism spectrum disorder,
hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations
in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited
duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated
with neurodevelopmental disorders. We performed an exome sequencing analysis on one
twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping
our patients’ phenotype.
Conclusions
This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder
even in the absence of epilepsy at an early age. It also highlights the necessity
to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic
variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order
to reach a correct diagnosis and provide the couple with a proper recurrence risk.
Abbreviations:
CNV (copy number variants), ID (intellectual disabilities), OFC (occipital frontal circumference), vnts (variants), MC (miscarriage), wg (weeks of gestation), ASD (autism spectrum disorders)Keywords
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References
- Genetics of early onset cognitive impairment.Annu Rev Genomics Hum Genet. 2010; 11: 161-187
- De novo mutations in moderate or severe intellectual disability.PLoS Genet. 2014; 10: e1004772
- Recurrent de novo mutations implicate novel genes underlying simplex autism risk.Nat Commun. 2014; 5: 5595
- Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.Lancet. 2012; 380: 1674-1682
- Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel–Giedion syndrome.J Med Genet. 2011; 48: 117-122
- Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies.Clin Genet. 2003; 63: 308-313
- CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.J Neurodev Disord. 2014; 6: 9
- Human copy number variation and complex genetic disease.Annu Rev Genet. 2011; 45: 203-226
- Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation.Hum Mutat. 2007; 28: 674-682
- The penetrance of copy number variations for schizophrenia and developmental delay.Biol Psychiatry. 2014; 75: 378-385
- Disease gene identification strategies for exome sequencing.Eur J Hum Genet. 2012; 20: 490-497
- CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures.Neurology. 2015; 84: 951-958
- The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res. 2010; 20: 1297-1303
- CHD2 mutations in Lennox–Gastaut syndrome.Epilepsy Behav. 2014; 33: 18-21
- Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.Nat Genet. 2013; 45: 825-830
- A maternally inherited 16p13.11-p12.3 duplication concomitant with a de novo SOX5 deletion in a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features.Am J Med Genet A. 2015; 167: 1315-1322
Article info
Publication history
Published online: January 02, 2016
Accepted:
December 11,
2015
Received in revised form:
December 6,
2015
Received:
June 18,
2015
Identification
Copyright
© 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
