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.

MACHADO-JOSEPH disease (MJD) is a progressive, adult-onset, neurodegenerative disorder transmitted in an autosomal dominant manner that affects the central nervous system. Its manifestations include cerebellar ataxia and progressive external ophthalmoplegia, associated in a variable degree with pyramidal signs, extrapyramidal signs (dystonia or rigidity), amyotrophy, and peripheral neuropathy.¹ The gene associated with this disease, MJD1, was cloned in 1994, and the causative mutation was shown to be the expansion of a (CAG)_n tract within its coding region.² This tract contains 12 to 44 triplets in healthy individuals and from 61 to 87 in patients, as shown in numerous studies of populations of diverse ethnic origin.^2-22