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Page 92 Khajuria et al. J Transl Genet Genom 2020;4:91-103 I http://dx.doi.org/10.20517/jtgg.2020.06

Conclusion: RTT is a childhood neurodevelopmental disorder primarily affecting females. It is caused by mutations
in the Methyl-CpG-Binding Protein 2 gene (MECP2 ), an important regulator of gene expression, located at
Xq28. Variants in MECP2 can be identified in 95%-97% of individuals with Classical RTT using a combination of
molecular techniques. This large cohort study from India showed the highest detection rate of MECP2 variants
in classical RTT patients, emphasizing the importance of using diagnostic criteria and having a multidisciplinary
team in the assessment of RTT patients, which can further help provide diagnostic testing, genetic counseling, and
prenatal testing.

Keywords: Rett syndrome, RTT, MECP2, DNA sequencing, genotype-phenotype correlations, mutation spectrum,
India

INTRODUCTION
Rett syndrome (RTT, OMIM #312750) is a childhood neurodevelopmental disorder primarily affecting
females. It is caused by mutations in the Methyl-CpG-Binding Protein 2 gene (MECP2, OMIM *300005),
[1]
an important regulator of gene expression, located at Xq28 .
Developmental regression is a hallmark of RTT, the ongoing pathology of which is still being unraveled.
Symptoms include loss of acquired skills, especially in relation to communicative and motor performance.
Clinical developmental profiles, non-specific early in life, become more specific later. To support clinical
diagnosis, a staging system has been developed as a framework that delineates the evolving symptoms. This
includes stages of early-onset stagnation, rapid developmental regression, a pseudo-stationary stage, and
late motor deterioration. We do not yet fully understand the biological pathways underlying the outward
[2]
presentations of the RTT . The multi-functionality of MECP2 suggests there are many downstream
pathways that are interesting for understanding the pathophysiology of RTT.

Variants in MECP2 can be identified in 95%-97% of individuals with Classical RTT, using a combination of
[3]
mutation detection techniques . Classical RTT is characterized by apparently normal early development,
arrest of developmental progress at 6-18 months followed by regression of social contact, language, and
hand skills. However, thereafter, improvements in social behavior and eye contact have been observed. The
[4]
most recent revision of the clinical criteria for diagnosis of RTT allows for a broader interpretation of
regression and partial recovery than was previously acknowledged and has led to increased understanding
of the disease . Clinicians should be aware of these criteria, for counseling of families as they seek to
[5]
understand the stages their child will encounter and for the application of management strategies that
may help to ameliorate or compensate for loss of skills at the different stages across the lifespan. A review
of the literature of mutation analysis in large cohorts of RTT patients in Western populations indicates
that the majority are sequence variations and only a small proportion of cases have large deletions/
[6,7]
duplications . To the best of our knowledge, there are only two studies on mutation spectrum of RTT
[8,9]
from India, including both typical and atypical RTT and until now no study has been reported on a large
cohort of classical RTT patients describing the spectrum of MECP2 sequence variations and to evaluate
the genotype-phenotype correlations based on the mutation spectrum. The objectives of the present
study were: (1) to study the clinical phenotype of Indian patients with classical RTT; (2) to identify the
spectrum of MECP2 sequence variations in a large cohort of Indian RTT patients and determine genotype-
phenotype correlation, if any; and (3) to predict the effects of MECP2 variations on MeCP2 Protein using
bioinformatics.

METHODS
Seventy-two sporadic classical RTT patients (all females) were included in this study from Pediatric OPD,
Pediatric wards, Pediatric Neurology and Medical Genetics services of the All India Institute of Medical