THE UTILITY OF WHOLE EXOME SEQUENCING
IN DIAGNOSING PEDIATRIC NEUROLOGICAL DISORDERS Muthaffar OY *Corresponding Author: Osama Y. Muthaffar, M.D., Department of Pediatrics, King Abdulaziz
University, Jeddah, PO Box 80215, Jeddah 21589, Kingdom of Saudi Arabia. Tel.: +96-12-640-1000
(ext. 20208). Fax: 996-12-640-3975. E-mail: oymuthaffar@kau.edu.sa; osamam@hotmail.com page: 17
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RESULTS
There were 19 males and seven females included in
the study. Age of presentation ranged from 1 to 12 years
(mean 4.8 years). Nineteen patients had positive WES
results (73.0%), five patients with variants of unknown significance
(VUS) that matches the clinical picture, one patient
with VUS that does not explain the observed clinical
characteristics. The remaining six patients were negative.
The average age in the WES-positive group was 4.9 years
and the average age in the WES-negative group was 4.5
years. Consanguinity was positive in 69.0% of the cohort,
most of them were in the WES-positive group (Table 2).
The WES-positive cohort results were classified into
pathogenic, likely pathogenic variants and VUS. In the homozygous
and heterozygous groups, pathogenic and likely
pathogenic mutations were found. These mutations, when
paired with the phenotype, confirms the clinical picture
(Tables 3 and 4). The VUS group was mainly clinically
upgraded to clinically significant variants as those patients
have matched genotype and phenotype. No benign or likely
benign variants were detected in this cohort.
Eight patients had homozygous mutations, six patients
had heterozygous mutations and six patients were
carrying VUS. All patients had variable neurological presentations
such as: epilepsy, intellectual delay, motor delay,
regression of milestones, hypotonia, visual abnormalities,
ataxia and MRI brain changes. Similar family history in
another sibling or relative was reported in seven patients
with positive WES result.
One patient had ITGA7 classified as VUS that does
not explain the phenotype. He was developmentally normal
then developed regression of milestones and a middle
cerebral artery stroke after meningoencephalitis. An
ITGA7 mutation was reported to be associated with congenital
muscular dystrophy, neonatal hypotonia, proximal
atrophy and scoliosis ,which were not apparent in this
patient before his regression.
Variants of unknown significance with consistent phenotypes
were seen in five patients (Table 3). The MLC1
mutation in patient #16 was consistent with megalencephalic
leukoencephalopathy with subcortical cysts type 1.
The patient developed ataxia and convulsions. Brain MRI
also showed expected white matter changes and temporal
cysts. Patient #17 had a SLC6A3 mutation compatible with
infantile Parkinsonism-dystonia type 1. He presented with
orolingual, upper and lower limbs dystonia and was initially
diagnosed as cerebral palsy. Patient #18 was diagnosed
with intractable infantile spasms and failed to respond to
multiple antiseizure medications for several months. He
also developed regression of milestones. A PNPO mutation was reported once. He was put on pyridoxal 5 phosphate
cofactor therapy. No more seizures were reported by the
parents and he is now developmentally up to age after 1
year of follow-up. Targeted analysis of both parents showed
heterozygous mutations in both (Figure 1). Patient #19 was
found to have ataxia and oculomotor apraxia. Brain MRI
showed classic molar tooth sign. The CC2D2A mutation
is associated with Joubert syndrome. Patient #20 had infantile
onset of developmental delay, hearing impairment,
hypotonia, visual impairment, focal epilepsy, high serum
lactic acid and brain MRI showed brain atrophy. Mutations
in SPATA5 and TIMMDC1 were reported to cause epilepsy,
hearing loss, and mental retardation syndrome and mitochondrial
complex I deficiency, respectively.
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