Focal cortical dysplasia, microcephaly and epilepsy in a boy with 1q21.1-q21.3 duplication

https://doi.org/10.1016/j.ejmg.2016.03.003Get rights and content

Abstract

The recent advance of new molecular technologies like array – Comparative Genomic Hybridization has fostered the detection of genomic imbalances in subjects with intellectual disability, epilepsy, and/or congenital anomalies. Though some of the rearrangements are relatively frequent, their consequences on phenotypes can be strongly variable. We report on a boy harbouring a de novo 8.3 Mb duplication of chromosome 1q21.1-q21.3 whose complex unusual phenotype deserves attention, due to the presence of focal cortical dysplasia, microcephaly, and epilepsy. Loss-of-function (LOF) effects of genes associated with human disease involved in the rearrangement have been only partially established, and have not been previously associated with brain malformations in several deletion syndromes. Less is known, instead, about the consequences of their duplication on neuronal migration and brain development process. Further advance in neuroimaging and genetic research will help in defining their actual role in neurodevelopment and cerebral cortex malformations.

Section snippets

Background

The recent advance of new molecular technologies like array Comparative Genomic Hybridization (CGH) has fostered the detection of new microdeletions and microduplications in subjects with intellectual disability (ID), epilepsy, and/or congenital anomalies. However, phenotypes associated with genomic imbalances are strongly variable, ranging from mild clinical features, that frequently remain overlooked, to severe psychomotor impairments and dysmorphic signs. In this perspective, when a new rare

Case presentation

The proband was born at term after uneventful pregnancy and delivery. His non-consanguineous parents, as well as two sisters, were healthy. At birth, weight was 3550 g (50th centile), length 52 cm (75th centile), and head circumference 33 cm (10th centile). Perinatal history was not contributory. From the age of two months, cranial growth had slowed up to reach the 3rd centile.

At 15 months he was admitted to IRCCS Stella Maris Scientific Institute for psychomotor delay and microcephaly, and

Cytogenetic analysis

Cytogenetic analysis was performed on G- and Q-banded chromosomes of peripheral blood lymphocytes, cultured and harvested according to standard techniques.

Array CGH

Genomic DNA of the patient was isolated from peripheral blood by standard methods; DNA from a healthy male was used as control (Agilent Technologies, Santa Clara, California). Two-hundred ng of genomic DNA both from the patient (test sample) and the control (reference sample) were digested with RSAI and ALUI restriction enzymes. Test and

Genomic rearrangement

Array CGH detected a 1q21.1-q21.3 duplication of about 8.3 Mb, ranging from position 144,927,578 to position 153,223,600 [UCSC genome Browser; http://genome.ucsc.edu/], hg 19 release (Fig. 2). The duplication encompassed more than 120 genes. In the context of the duplication, two oligos in position 149079747–149224043 showed mean fluorescent ratio values compatible with a homozygous deletion. This region encompasses NBPF25P and NBPF23 genes.

Array CGH profiles from the parents were normal.

Discussion and conclusions

We report on a child with focal cortical dysplasia, microcephaly, epilepsy and ID, harbouring a de novo 8.3 Mb duplication of 1q21.1-q21.3 chromosome. The imbalances of the 1q21.1 region have been largely described, while less data are available on the adjacent region 1q21.2-q21.3 [https://decipher.sanger.ac.uk/]. Region 1q21.1 is structurally complex and contains several SDs, whose localization has been modified in the different genome versions. These SDs facilitate mispairing and non-allelic

Consent

Written informed consent was obtained from patient's parents for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Conflict of interest

The Authors declare non-financial competing interests.

Author's contribution

Study concept and design: RM, RB, AV, FS.

Acquisition of data: RM, AV, VB, RB, GV, FS.

Draughting of the manuscript: RM, RB, AV, VB, GV, FS.

Analysis and interpretation of data: RM, RB, AV, VB, GC, FS.

Critical revision of the manuscript for important intellectual content: RB, FS, GC.

All authors read and approved the final version of the manuscript to be published and they agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any

References (24)

  • G.M. Cooper et al.

    A copy number variation morbidity map of developmental delay

    Nat. Genet.

    (2011)
  • M. Fanciulli et al.

    Copy number variations and susceptibility to lateral temporal epilepsy: a study of 21 pedigrees

    Epilepsia

    (2014)
  • Cited by (0)

    View full text