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. 2016 Mar;53(3):190-9.
doi: 10.1136/jmedgenet-2015-103568. Epub 2016 Jan 6.

Identification of novel genetic causes of Rett syndrome-like phenotypes

Fátima Lopes  1 , Mafalda Barbosa  2 , Adam Ameur  3 , Gabriela Soares  4 , Joaquim de Sá  5 , Ana Isabel Dias  6 , Guiomar Oliveira  7 , Pedro Cabral  8 , Teresa Temudo  9 , Eulália Calado  6 , Isabel Fineza Cruz  10 , José Pedro Vieira  6 , Renata Oliveira  5 , Sofia Esteves  1 , Sascha Sauer  11 , Inger Jonasson  3 , Ann-Christine Syvänen  12 , Ulf Gyllensten  3 , Dalila Pinto  13 , Patrícia Maciel  1
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Free article

Identification of novel genetic causes of Rett syndrome-like phenotypes

Fátima Lopes et al. J Med Genet. 2016 Mar.
Free article

Abstract

Background: The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach.

Methods and results: We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT.

Conclusions: Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

Keywords: Epilepsy; Intellectual disability; Rett syndrome; Whole exome sequencing.

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