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Khajuria et al. J Transl Genet Genom 2020;4:91-103 I http://dx.doi.org/10.20517/jtgg.2020.06 Page 99

Table 4. Genotype-phenotype correlations of RTT patients based on the profile of common sequence variants
p.T158M p.R270X p.R168X p.R255X p.R133C p.R306C p.G269fs
Clinical features
(n = 8) (n = 8) (n = 7) (n = 5) (n = 5) (n = 5) (n = 5)
AD (months)
Mean ± SD 37.9 ± 15 57.8 ± 55.5 58.3 ± 36.9 56.4 ± 16.8 55.2 ± 22.2 49.2 ± 9.9 69.8 ± 60.8
Median (IQR) 36 (21-72) 33 (18-186) 60 (18-186) 48 (42-84) 60 (30-84) 54 (36-60) 54 (19-168)
AO (months)
Mean ± SD 16.5 ± 3.7 13 ± 2.1 13.9 ± 5.6 16.4 ± 3.3 20 ± 3.7 16.8 ± 5.8 16.4 ± 3.3
Median (IQR) 16 (12-24) 12 (12-18) 14 (12-18) 18 (12-20) 18 (16-24) 18 (8-24) 18 (12-20)
Speech problem 8 8 7 5 5 5 5
Hand stereotypes 8 8 7 5 5 5 5
Some hand/finger use 0 0 0 0 1 2 0
Microcephaly 5 7 6 5 4 3 4
Neuroregression 6 6 6 5 5 5 5
Constipation 6 1 6 4 0 1 1
Walking capability
Ataxic 3 2 2 1 5 4 2
With support 3 1 2 0 0 1 2
No 2 5 3 4 0 0 1
Breathing problems 3 4 2 3 2 3 2
Abn imaging study 0 0 0 0 1 2 1
Abn muscle tone 2 4 2 0 2 1 2
Muscle atrophy 3 4 2 3 0 1 1
Growth retardation 7 5 4 4 1 1 3
Sleep problem 5 5 3 5 3 2 3
Abn EEG 2 4 3 5 3 2 2
Seizures 2 4 3 3 3 1 2
Scoliosis 1 5 3 3 0 0 1
Hearing impairment 0 0 1 0 0 1 1
Mild dysmorphism 0 2 2 2 0 0 0
Opthal. impairment 0 0 0 1 0 1 0
Mortality 1 0 0 2 0 1 0
AD: age at diagnosis; AO: age at onset; SD: standard deviation; IQR: inter-quartile range; Abn: abnormal; Opthal: ophthalmological; RTT:
Rett syndrome

The mortality was also higher in RTT patients with nonsense variants than missense variants, although
we were unable to find any statistical significance due to small number of patients. Most of the missense
sequence variations in our study were clustered in MBD of MeCP2 and the early truncating sequence
2
variations were similarly clustered in TRD of MeCP2 (Pearson χ test; P = 0.000).

DISCUSSION
Until now, few reports on variant analysis of MECP2 gene in classical RTT have been published from
India [8,9,15] , thus there are scarce data regarding mutation spectrum and genotype-phenotype correlations.
The present study evaluated 72 Classical RTT females based on the revised diagnostic criteria and
revealed a heterogeneous spectrum of sequence variants including 13 novel variants with a detection
rate of 98.6% using a combination of Sanger sequencing and MLPA, which is higher compared to other
studies on mutation spectrum of RTT. The results of the present study emphasize the need for a careful
and meticulous clinical evaluation that is likely to select appropriate cases with a good yield on molecular
testing, which is important in resource constrained settings.

It has been reported that MECP2 variants can be detected with a frequency of more than 95%-97% in
classical RTT by screening coding region and flanking intronic regions of MECP2 gene using PCR based
techniques [3,16] , but these methods do not detect gross rearrangements, which could be present in a
[5]
significant proportion of classical RTT patients . Several groups have identified gross rearrangements using
quantitative analysis of MECP2 using MLPA in the patients where the cause of RTT remains unknown after
sequencing [6,13,14,17] .