The utility of whole exome sequencing in diagnosing pediatric neurological disorders

OY Muthaffar

doi:10.2478/bjmg-2020-0028

Figures & Tables

Parents of a child with an inherited PNPO gene mutation. They are cousins and both are heterozygous. A) Mother; B) father.

Brain MRI in a child with acute necrotizing encephalopathy and a positive RANBP2 gene mutation. Brain MRI showing increased T2 hyperintensity of basal ganglia (A, B, and C).

Homozyogous, heterozygous and variants of uncertain significance VUS groups_

Homozygous Mutations
#	Sex-Age	Family History	Consanguinity	Clinical Characteristics	Onset	Genes	Variant	Diagnoses
1	F-6	yes	yes	motor delay; hypotonia; scoliosis; respiratory difficulties in neonatal period; normal congnitions, areflexia	1 year	P1EZO2	pathogenic: c.273_279del, p.(Pro92Thrfs*18)	piezo-type mechanosensitive ion channel component; OMIM: 613629
2	M-1	no	yes	severe hypotonia; reduced tendon reflexes; motor/speech delay; cerebellar atrophy; cerebellar cyst; elevated serum CPK	birth	FKRP	likely pathogenic: c.204del, p.(Ser69Profs*60)	MDDGA5 (congenital with brain/eye anomalies), type A5 (MDDGA5); OMIM: 613153
3	M-2	no	yes	vision loss; nystagmus; severe retinal dysfunction	2 months	RPGRIP1	pathogenic: c.1107del, p.(Glu370Asnfs*5)	Leber congenital amaurosis type 6, OMIM: 613826
4	M-7	no	yes	intractable epilepsy; global developmental delay; poor vision	3 years	TPP1	pathogenic: c.616C>T, p.(Arg206Cys)	neuronal ceroid lipofuscinosis type 2, OMIM: 204500
5	M-8	no	yes	poor hearing; encephalopathy; MRI: white matter changes	4 years	BTD	pathogenic: c.1618C>T, p.(Arg540Cys)	biotinidase deficiency
6	M-6	yes	yes	ataxia; delayed motor milestones; mild intellectual delay; MRI: cerebellar atrophy	1 year	SPTBN2	likely pathogenic: c.6258_6261delGAGA, p.(Lys2088Glyfs*228)	infantile-onset spinocerebellar ataxia type 5
7	F-8	yes	yes	ataxia; delayed motor milestones; mild intellectual delay; MRI: cerebellar atrophy	1 year	SPTBN2	likely pathogenic: c.6258_6261delGAGA, p.(Lys2088Glyfs*228)	infantile-onset spinocerebellar ataxia type 5
8	M-9	yes	yes	ataxia; oculomotor apraxia; telangiectasia; MRI: cerebellar atrophy	3 years	ATM	likely pathogenic: c.9066del, p.(Gly3023Alafs*10)	ataxia telangiectasis
Heterozygous Mutations
9	F-7	no	no	delayed language/motor development; intellectual disability; hypotonia; generalized seizures; infantile spasms; visual impairment; normal MRI; normal metabolic profile	1 year	NTRK2	pathogenic: c.1301A>G, p.(Tyr434Cys)	early infantile epilectic encephalopathy type 58, OMIM: 617830
10	M-3	yes	no	acute necrotizing encephalopathy; generalized seizures; spasticity; coma and death; brain MRI: symmetric thalamic hyperintense lesions	3 years	RANBP2	pathogenic: c.1754C>T, p.(Thr585Met)	acute infection-induced encephalopathy-type 3, OMIM: 608033
11	M-4	no	no	developmental delay; neonatal hypotonia; autistic-like behavior; epilepsy	1 year	SHANK3	likely pathogenic: c.2313+1G>A	Phelan-McDermid syndrome, OMIM: 606232
12	M-9	no	no	ataxia; ADHD; delayed speech/ language development; motor delay; hypotonia; normal EEG and brain MRI	2 years	KAT6A	likely pathogenic: c.1483-1G>A	mental retardation type 32, OMIM: 616268
13	M-1	no	no	intractable neonatal seizures; normal brain MRI	1 month	PACS2	pathogenic: c.625G>A, p.(Glu209Lys)	early infantile epileptic encephalopathy type 66, OMIM: 618067
14	F-4	no	yes	intractable focal seizures; normal brain MRI	3 months	SCN1A	likely pathogenic: c.1377G>C, p.(Gln459His)	early infantile epileptic encephalopathy type 6 (Dravet syndrom), OMIM: 607208
Variant(s) of Uncertain Significance
15	M-6	no	yes	MCA stroke; dystonia; spasticity; regression of milestones; delayed language/ motor development; focal seizures and abnormal brain myelination on MRI	4 years	ITGA7 AR	c.1601C>T, p.(Ala534Val)	congenital muscular dystrophy/hypotonia, OMIM: 613204
16	F-5	no	yes	ataxia; frequent falls; macrocephaly, epilepsy and ADHD; MRI: megalencephalic leukoencephalopathy with subcortical cysts	2 years	MLC1 AR	c.275C>A, p.(Pro92His)	megalencephalic leukoencephalopathy with subcortical cysts type 1, OMIM: 604004
17	M-3	no	yes	delayed speech/language development; dyskinesia; dystonia; infantile onset of the disease; paroxysmal dystonia; MRI: brain atrophy	2 years	SLC6A3 AR	c.851G>A, p.(Gly284Glu)	infantile Parkinsonism dystonia type 1, DTDS, PMID: 21777827
18	M-1	yes	yes	intractable infantile spasms	3 months	PNPO AR	c.256T>C, p.(Cys86Arg)	PNPO, OMIM: 603287
19	F-6	yes	yes	ataxia and oculomotor apraxia; brain MRI: molar tooth sign	2 years	CC2D2A AR	c.916_927del, p.(Pro306_Leu309del)	Joubert syndrome type 9, OMIM: 612285
20	M-2	no	yes	fair hair; global developmental delay; hearing impairment; infantile onset of the disease; motor delay; muscular hypotonia; visual impairment; focal epilepsy; MRI: brain atrophy	3 months	SPATA5 AR and TIMMDC1^a	c.1058A>T, p.(Asp353Val) and c.230T>C, p.Ile77Thr)	EHLMRS, OMIM: 616577 mitochondrial complex I deficiency, OMIM: 618251

Cohort demographics: WES positive and negative_

	Positive n (%)	Negative n (%)
Males	14	5
Females	6	1
Total	20 (77.0)^a	6 (23.0)
Age (mean)	4.9 years	4.5 years
Consanguinity	14 (53.0)	4 (15.0)

Whole exome sequencing negative group_

#	Sex-Age	Family History	Consanguinity	Clinical Characteristics	Onset
1	F-1	no	yes	epilepsy and developmental delay; brain MRI: normal	4 months
2	M-7	no	yes	epilepsy and developmental delay; brain MRI: normal	2 years
3	M-2	no	no	intractable epilepsy; poor vision and global developmental delay; brain MRI: normal	1 year
4	M-12	no	yes	global developmental delay; brain MRI: basal ganglia enhancement; metabolic work-up: negative	6 years
5	M-4	yes	yes	intractable focal epilepsy and ADHD	1 year
6	M-2	no	yes	microcephaly; motor delay; brain MRI: white matter changes	6 months

American College of Medical Genetics and Genomics (ACMG) classification of variants [17]_

Class 1	Pathogenic
Class 2	Likely pathogenic
Class 3	Variant of uncertain significance (VUS)
Class 4	Likely benign
Class 5	Benign

The utility of whole exome sequencing in diagnosing pediatric neurological disorders

Figures & Tables

Figure 1

Figure 2

Homozyogous, heterozygous and variants of uncertain significance VUS groups_

Cohort demographics: WES positive and negative_

Whole exome sequencing negative group_

American College of Medical Genetics and Genomics (ACMG) classification of variants [17]_

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