Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders

Figures & data

Figure 1 Genetic pleiotropy of amyotrophic lateral sclerosis (ALS) genes. The figure is based on information from Online Mendelian Inheritance in Man (OMIM) (19), GeneReviews (20) and the study by Goutman et al. “Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis” (21). Abbreviations: SMA = spinal muscular atrophy; PLS = primary lateral sclerosis; HSP = hereditary spastic paraplegia.

Figure 2 Overview of methods and variant interpretation. DMs = disease-causing mutations, HGMD = the Human Gene Mutation Database, MAC = minor allele count.

Figure 3 Neuromuscular or neurodegenerative disorders among the relatives of patients with amyotrophic lateral sclerosis (ALS). Left circle: patients with ALS (n = 279) reporting relatives with or without other neuromuscular or neurodegenerative disorders. Right circle: neuromuscular and neurodegenerative disorders reported among relatives of the 85 patients with ALS and a positive family history. Four cases had relatives with both PD and dementia; these individuals are shown twice in the right circle. Abbreviation: NMD or NDD = neuromuscular or neurodegenerative disorders.

Table 1 Variants identified from the genetic analysis of 510 genes known to cause neuromuscular and neurodegenerative disorders.

Case No.	Gene	Associated phenotype	Zyg-osity	cDNA change	Protein change	Frequency			REVEL^2	Previous identifications
						gnomAD (AC)	In-house OUS^1 (AC)	Project Mine cases/control		ClinVar		HGMD
										Access.	Interpret.	Access.
	Neurodegenerative disorders
1	AFG3L2	Ataxia	Het	NM_006796.3:c.1363C > T	p.(Arg455*)	–	–	–	–	810710	LP	–
2	KIF1A	HSP	Het	NM_001244008.2:c.532G > A	p.(Val178Met)	1/248966	–	1/0	0.734	2170690	VUS	–
3	KIF1A	HSP	Het	NM_001244008.2:c.1856C > G	p.(Ala619Gly)	–	–	–	0.352	–	–	–
4	KIF1A	HSP	Het	NM_001244008.2:c.2131C > T	p.(Arg711Trp)	2/245586	–	–	0.491	850488	VUS	–
5 6	LRRK2	PD	Het	NM_198578.4:c.6055G > A	p.(Gly2019Ser)	138/282542	1/25748	2/0	0.97	1940	P-LP-RF	CM050659
7 8	MSTO1	Mit.dis.	Het	NM_018116.4:c.966 + 1G > A	p.?	2/245702	–	–	–	438834	LP	CS1710302
9 10	NEK1	ALS risk	Het	NM_001199397.3:c.379C > T	p.(Arg127*)	7/222006	–	1/0	–	30428	P	CM110308
11 12 13 14	NEK1	ALS risk	Het	NM_001199397.3:c.3107C > G	p.(Ser1036*)	33/280416	23/25748	22/0	–	208600	P-LP	CM173447
15	NEK1	ALS risk	Het	NM_001199397.3:c.3715-6G > A	p.?	–	–	–	–	–	–	–
16	SORL1	AD	Het	NM_003105.6:c.1016_1020del	p.(Gln339Argfs*7)	–	–	–	–	–	–	–
17	SORL1	AD	Het	NM_003105.6:c.4519 + 1G > A	p.?	–	–	–	–	–	–	CS1719333
	Neuromuscular disorders
18	ATL3	Sens.neuro	Het	NM_015459.5:c.484C > G	p.(Leu162Val)	1/248592	–	–	0.831	1046127	VUS	–
19	ATP7A	SMA	Hemi	NM_000052.7:c.2957G > A	p.(Arg986Gln)	2/183362	–	–	0.718	245881	VUS	CM078711
20	ATP7A	SMA	Hemi	NM_000052.7:c.3007T > C	p.(Ser1003Pro)	–	–	–	0.844	1722297	VUS	–
21	BICD2	SMA	Het	NM_001003800.2:c.793A > C	p.(Met265Leu)	–	8/25748	–	0.151	1426770	VUS	–
22	BICD2	SMA	Het	NM_001003800.2:c.793A > G	p.(Met265Val)	8/282854	2/25748	–	0.192	1398905	LB	CM1820695
23	BICD2	SMA	Het	NM_001003800.2:c.1317C > G	p.(Tyr439*)	–	–	–	–	–	–	–
24	HARS1	CMT	Het	NM_002109.6:c.344A > G	p.(Tyr115Cys)	1/251238	–	–	0.811	–	–	–
25	NEFH	CMT/ ALS risk	Het	NM_021076.4:c.841C > G	p.(His281Asp)	–	–	–	0.725	1305764	VUS	–
19	NEFH	CMT/ ALS risk	Het	NM_021076.4:c.2404C > T	p.(Pro802Ser)	–	–	–	0.213	–	–	–

Abbreviations: 1-allele frequency from a Norwegian in-house hospital database (Department of Medical Genetics, Oslo University hospital) obtained from families referred for genetic analysis of various disorders. 2-REVEL is an in silico tool used for predicting the pathogenicity of missense variants. The score can range from 0 to 1, with higher scores indicating a higher possibility that the variant is disease causing (25). AC = allele count; Access. = Accession; AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; CMT = Charcot–Marie–Tooth disease; dis = disorder; Het = heterozygous; Hemi = hemizygous; HSP = hereditary spastic paraplegia; Interpret. = interpretation; LB = likely benign; LP = likely pathogenic; Mit. = mitochondrial; P = pathogenic; PD = Parkinson’s disease; RF = risk factor; Sens.neuro = sensory neuropathy; SMA = spinal muscular atrophy; VUS = variant of uncertain significance.

Table 2 Patient phenotypes at inclusion.

Case No.	Gender	ALS type	Relatives ^w/NMD or NDD (type)	Relative degree	Age of onset	# years from onset to diagnosis	Site of onset	Bulbar signs	UMN signs	LMN signs	Sensory symptoms	Cognitive affection	Neurological findings consistent with ALS	El Escorial fulfilled
1	F	sALS	–	–	70–80	NA	S	Y	Y	–	–	–	Y	Y
2	M	sALS	–	–	30–40	3	S	–	Y	Y	–	Y	Y	Y
3	F	sALS	–	–	50–60	2	S	–	–	Y	–	–	Y	U
4	F	sALS	–	–	60–70	0	S	–	Y	Y	–	–	Y	Y
5	F	sALS	Y (NA)	NA	70–80	1	S	Y	Y	Y	–	–	Y	Y
6	M	sALS	–	–	60–70	2	Both	Y	Y	Y	Y	–	Y	Y
7	F	sALS	Y (PD)	1^st	30–40	1	S	–	Y	Y	–	–	Y	Y
8	F	sALS	–	–	70–80	0	B	Y	–	Y	–	–	Y	Y
9	M	sALS	–	–	60–70	1	S	–	Y	Y	–	–	Y	Y
10	M	sALS	–	–	50–60	1	S	–	U	Y	–	–	U	–
11	M	sALS	Y (NA)	NA	50–60	3	S	–	Y	Y	–	–	Y	Y
12	M	fALS	–	–	70–80	1	S	–	U	Y	–	–	Y	Y
13	M	sALS	–	–	70–80	1	Both	Y	Y	Y	–	–	Y	Y
14	F	sALS	–	–	40–50	1	B	Y	Y	Y	–	–	Y	Y
15	M	sALS	–	–	50–60	0	S	–	Y	Y	–	–	Y	Y
16^A	F	sALS	–	–	60–70	7	S	Y	Y	–	–	–	–	–
17	F	sALS	–	–	50–60	3	S	Y	Y	Y	–	–	Y	Y
18	M	sALS	–	–	50–60	1	S	–	Y	Y	Y	–	Y	Y
19	M	sALS	–	–	30–40	1	S	–	Y	Y	–	–	Y	Y
20	M	sALS	Y (NA)	NA	60–70	1	Both	Y	Y	Y	–	U	Y	Y
21	M	sALS	–	–	70–80	3	S	–	Y	Y	–	Y	Y	Y
22	M	sALS	–	–	50–60	1	S	–	Y	Y	–	–	Y	Y
23	F	sALS	–	–	40–50	1	Both	Y	Y	Y	–	–	Y	U
24	F	sALS	–	–	60–70	3	S	–	–	Y	–	–	Y	–
25	M	sALS	–	–	60–70	1	B	Y	Y	Y	–	–	Y	Y

Abbreviations: A = Patient diagnosed with PLS; ALS = amyotrophic lateral sclerosis; B = bulbar; D = dementia; F = female; fALS = familial ALS; LMN = lower motor neuron; M = male; NA = not available; NDD = neurodegenerative disorder; NMD = neuromuscular disorder; PD = Parkinson’s disease; S = spinal; sALS = simplex ALS; U = uncertain; UMD = upper motor neuron; Y = yes.

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Data availability statement

Data supporting the findings of this study are available from the corresponding author upon request.