Rett and Rett-like disorders
Breda Genetics panel recommended for this conditions:
Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting the central nervous system. Being most frequently transmitted as an X-linked dominant disorder caused by MECP2 mutations (90% of cases), RTT primarily affects females, making it one of the most common genetic causes of severe intellectual disability in females. Prevalence is estimated at 1/9,000 in females and 1/30,000 in the general population (males and females). RTT can be seen in typical and atypical forms. Typical RTT is caused by mutations in the MECP2 gene. Atypical RTT can be caused by mutations in the FOXG1, CDKL5, MEF2C and TCF4 gene. Recently whole exome sequencing aided in identifying mutations in at least three additional genes in patients with clinical features resembling RTT: GABRD, WDR45, SMC1A.
The newly identified genes
In the GABRD gene Okamoto et al, 2014 (PMC: 4500929) found two mutations affecting two adjacent codons: c.498G > A: p.Met166Ile and c.499G > A: p.Asp167Asn. The patient had severe intellectual disability, hypotonia, stereotypic behaviour, inability to walk independently and severe language impairment.
In a Japanese girl initially reported to have an RTT-like phenotype, a mutation has been identified in the WDR45 gene (Okamoto et al. 2014, PMC: 4500929). The variant was a heterozygous de novo nonsense mutation causing protein truncation (c.868C > T: p.Gln290*). Symptoms appeared after the 10th month as stereotypic hand-wringing and finger-sucking behavior typical of RTT. Seizures, delayed myelination and enlarged lateral ventricles appeared later.
Another patient with RTT-like symptoms was identified to have a single exon deletion in the SMC1A gene, of which mutations have been so far linked to Cornelia de Lange syndrome. This patient showed a mix of symptoms and signs both typical (microcephaly, stereotypic movements) and atypical (dysmorphisms and brain MRI abnormalities) for RTT. (Gilissen et al. 2014, PMC: 4500929)
Of note, the GABRD, WDR45, SMC1A, MEF2C and TCF4 gene mutations are not reported in the RettBASE database.
Breda Genetics srl
Following this evidence, Breda Genetics srl has set up a new, dedicated panel:
If this panel comes out negative (both for sequencing and deletion/duplication testing), we recommend the upgrade to full exome.
The Utility of Next-Generation Sequencing in Gene Discovery for Mutation-Negative Patients with Rett Syndrome. Gold WA, Christodoulou J. Front Cell Neurosci. 2015 Jul 14;9:266. PMID: 26236194
Rett syndrome: insights into genetic, molecular and circuit mechanisms. Ip JPK, Mellios N, Sur M. Nat Rev Neurosci. 2018 Jun;19(6):368-382. PMID: 29740174
Rett Syndrome. Chahil G, Bollu PC. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018-. 2018 Oct 27. PMID: 29489169
Rett syndrome from bench to bedside: recent advances. Ehinger Y, Matagne V, Villard L, Roux JC. F1000Res. 2018 Mar 26;7:398. PMID: 29636907
Rett syndrome: a neurological disorder with metabolic components. Kyle SM, Vashi N, Justice MJ. Open Biol. 2018 Feb;8(2). PMID: 29445033
Clinical and biological progress over 50 years in Rett syndrome. Leonard H, Cobb S, Downs J. Nat Rev Neurol. 2017 Jan;13(1):37-51. PMID: 27934853
Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes. Ehrhart F, Coort SL, Cirillo E, Smeets E, Evelo CT, Curfs LM. Orphanet J Rare Dis. 2016 Nov 25;11(1):158. PMID: 27884167