Genetic Diagnosis in Movement Disorders. Use of Whole-Exome Sequencing in Clinical Practice

Patricio Millar Vernetti; María Agustina Ruiz Yanzi; Malco Rossi; Marcelo Merello

doi:10.5334/tohm.678

Figures & Tables

Table 1

Findings in patients evaluated with WES: phenotype, age at time of study, genetic test results, homo or heterozygosity, family history, and treatment.

PHENOTYPE/PATIENT	ATAXIA	PARKINSONISM	TREMOR	SPG	DYSTONIA	AGE AT WES (YRS.)	LATENCY FROM THE ONSET OF SYMPTOMS (YRS.)	FINDING	INTERPRETATION	VARIANT	DIAGNOSIS	AVAILABLE TREATMENT	HOMOZYGOUS OR HETEROZYGOUS	FAMILY HISTORY
1		+				27	5	V/V	V/V	FBN1 c.8149G>A(p.Glu2717Lys) + TSC2 c.2245C>T(p.Arg749Trp)	.	NO	Heterozygous	NO
2					+	65	5	V	V	KMT2B c.2068G>C((p.Glu690Gln)	DYT28	GPi DBS [19]	Heterozygous	NO
3				+		66	14	V	V	SETX c.628A>G (p.Ile210Val)	ALS type 4	NO	Heterozygous	NO
4					+	31	13	V	V	ITPR1 c.5149C>A (p.Leu1717Met)	.	NO	Heterozygous	NO
5	+	+				70	10	V	V	GRN c.421G>A (p.Val141Ile)	FTD	NO	Heterozygous	NO
6	+	+				72	2	V	V	CCDC88C c.2491G>A (p.Glu831Lys)	.	NO	Heterozygous	YES (father)
7					+	25	2	V	V	COL4A1 p.(Glu1539Gly)	.	NO	Heterozygous	NO
8			+			72	72	V	P	GDAP c.818G>A (p.Arg273Gln)	CMT 2K	NO	Homozygous	YES (son)
9	+				+	22	7	V	P	POLG c.818G>A (p.Arg273Gln)	CPEO	L-DOPA [18], avoid valproic acid, use of ATQ3 [20]	Heterozygous	NO
10	+					58	10	V	P	MFN2 c.187A>C (p.Asn63His)	CMT 2A2A	NO	Heterozygous	NO
11					+	71	21	V	V	DDC c.73G>A (p.Glu25Lys)	AADC deficiency	Dopaminergic agonists, MAOIs, vitamin B6 [21]	Heterozygous	NO
12		+		+		53	10	V	V	CHMP2B c.581C>T (p.Ser194Leu).	ALS type 17	NO	Heterozygous	NO
13		+				49	4	V	V	C9orf72 c.80G>A (p.Arg27Gln)	ALS + FTD	NO	Heterozygous	NO
14	+					73	3	V	P	ELOVL5 c.327+1G>A	SCA 38	DHA [14]	Heterozygous	NO
15	+			+		74	–	V	V	PRPH c.421G>T (p.Asp141Tyr) + c.870+5A>G	ALS	NO	Compound heterozygous	YES (sister)
16	+					33	–	V	V	OPA1 c.1397C>T (p.Ala466Val)	DOA	NO	Heterozygous	NO
17	+				+	93	6	V	V	SETX c.3436A>G (p.Ser1146Gly)	.	NO	Heterozygous	NO
18					+	25	23	V	V	AUTS2 c.2972A>C (p.Asp991Ala)	.	NO	Heterozygous	NO
19	+					23	17	P/V	P for deafnessV for ataxia	MYO15A c.8003_8004insA(p.Thr2669Hisfs*43) + c.387A>C(p.Lys129Asn)	MYO15A	NO	Compound heterozygous	NO
20		+				63	3	P/V	V	VPS13A c.1115dup (p.Leu373Valfs*4) + VPS13C c.5209G>A (p.Ala1737Thr)	Juvenile PD (parkin)	NO	Compound heterozygous	NO
21		+				65	25	P	P	PRKN c.155del (p.Asn52Metfs*29) + c.823C>T (p.Arg275Trp)	Juvenile PD (parkin)	NO	Compound heterozygous	YES(father)
22			+			20	3	P	P	PRKN c.823C>T(p.Arg275Trp) + c.535-2A>C	Juvenile PD (parkin)	Trihexyphenidyl [16], Levodopa [22], DBS [23]	Compound heterozygous	YES(brother)
23		+				56	10	P	P	GRN c.1562G>A (p.Cys521Tyr)	FTD	NO	Heterozygous	NO
24		+				55	4	P	P	CYP27A1 c.1183C>T (p.Arg395Cys) + c.1214G>A (p.Arg405Gln)	CTX	CDCA [13]	Compound heterozygous	NO
25	+					34	20	P	P	SPG7 c.1A>G (p.Met1?) + c.1529C>T (p.Ala510Val)	SPG7	NO	Compound heterozygous	NO
26	+	+			+	29	6	P	P	ATP1A3 c.1877C>T (p.Thr626Met)	DYT12	Avoid triggers, use of flunarizin [12, 24]	Heterozygous	Unknown(adopted)
27			+			31	5	P	P	CYP27A1 c.421G>T (p.Asp141Tyr)	CTX	CDCA [13]	Heterozygous	NO
28	+				+	32	32	P	P	PMM2 c.722G>C (p.Cys241Ser) + c.422G>A(p.Arg141His)	CDG-Ia	Acetazolamide [15]	Compound heterozygous	YES(sister case 29)
29	+				+	35	35	P	P	PMM2 c.722G>C (p.Cys241Ser) + c.422G>A(p.Arg141His)	CDG-Ia	Acetazolamide [15]	Compound heterozygous	YES(sister case 28)
30				+		57	–	P	P (for Rippling muscle disease)	CAV3 c.80G>A (p.Arg27Gln)	LGMD	NO	Heterozygous	YES(maternal cousin, aunt, uncles and grandfather)
31					+	32	27	P	P	THAP1 c.505C>T(p.Arg169*)	DYT6	GPi DBS [25]	Heterozygous	YES(mother, maternal grandmother and aunt)
32					+	29	29	P	P	KMT2B c.165del (p.Pro56Argfs*111)	DYT28	GPi DBS [19]	Heterozygous	NO

[i] Crosses (+) indicate presence of a given phenotype in each patient; AADC (aromatic L-amino acid decarboxylase), ALS (Amyotrophic Lateral Sclerosis), ATQ3 (α-tocotrienol quinone), CDCA (chenodeoxycholic acid), CDG-Ia (Congenital Disorder of Glycosylation type Ia), CMT (Charcot-Marie-Tooth), CPEO (Chronic Progressive External Ophthalmoplegia), CTX (Cerebrotendinous Xanthomatosis), DHA (docosahexaenoic acid), DOA (Dominant Optic atrophy), DYT (dystonia), FTD (Frontotemporal Dementia), GPi DBS (Deep Brain Stimulation of the Globus Pallidus interna), LGMD (Limb-Girdle Muscular Dystrophy), MAOIs (monoamine oxidase inhibitors), MYO15A (autosomal recessive hearing loss, ataxia and polyneuropathy), P (Pathogenic), PD (Parkinson’s Disease), SPG (spastic paraplegia), V (Variant of Unknown Significance).

Supplementary Table 1

Treatments indicated based on current evidence and patient clinical outcomes. SARA: Scale for the assessment and rating of ataxia.

PATIENT	MUTATION	DIAGNOSIS	TREATMENT	CLINICAL IMPROVEMENT
12	POLG c.818G>A (p.Arg273Gln)	Chronic Progressive External Ophthalmoplegia	Antioxidants, levodopa	Yes (mild, partial and transient)
21	DDC c.73G>A (p.Glu25Lys)	AADC (aromatic L-amino acid decarboxylase) deficiency	Rasagiline, ropinirole, vitamin B6	No
25	ELOVL5 c.327+1G>A	Spinocerebellar ataxia type 38 (SCA38)	Omega-3	Yes (reduction in SARA score, from 11 to 5 points)
4	PRKN c.823C>T(p.Arg275Trp) + c.535-2A>C	Juvenile Parkinson’s disease	Trihexyphenidyl	Yes (almost complete tremor resolution)
15	CYP27A1 c.1183C>T (p.Arg395Cys) + c.1214G>A (p.Arg405Gln)	Cerebrotendinous xanthomatosis	Chenodeoxycholic acid	No (insufficient doses due to lack of treatment availability)
18	CYP27A1 c.421G>T (p.Asp141Tyr)	Cerebrotendinous xanthomatosis	Chenodeoxycholic acid	Yes (mild, partial and transient)
17	ATP1A3 c.1877C>T (p.Thr626Met)	Dystonia 12	Avoidance of triggers	Yes (partial)
19	PMM2 c.722G>C (p.Cys241Ser) + c.422G>A(p.Arg141His)	Congenital Disorder of Glycosylation type Ia	Acetazolamide	Yes (mild and partial improvement in gait ataxia)
20	PMM2 c.722G>C (p.Cys241Ser) + c.422G>A(p.Arg141His)	Congenital Disorder of Glycosylation type Ia	Acetazolamide	No

Genetic Diagnosis in Movement Disorders. Use of Whole-Exome Sequencing in Clinical Practice

Figures & Tables

Table 1

Supplementary Table 1

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