Genotype-phenotype correlations of KIF5A stalk domain variants

Figures & data

Figure 1 Pedigree of examined family including genotype/phenotype information. Females are represented by circles and males by squares. The proband is marked with an arrow and * indicates the cases that have a known genotype. Sequence chromatogram of proband, his father, and sister showing the c.1702G > A variant (bold).

Figure 2 Localization of reported KIF5A variants within the different regions of the gene and the phenotypes associated with them. Variants with an allele frequency above 1/1000 in gnomAD v2.1.1 are in gray. ALS: amyotrophic lateral sclerosis; CMT2: Charcot-Marie-Tooth; NEIMY: neonatal intractable myoclonus; SPG: spastic paraplegia.

Table 1 Reported KIF5A stalk variants.

		KIF5A variant					Phenotype
	Nucleotide	AA change	gnomAD allele count/number (allele frequency) ^a	dbSNP rsID	ACMG classification	CADD Score (PHRED)	Age of onset (year)	Main phenotype	Additional symptoms	Source
1	c.967C > T	p.(Arg323Trp)	1 /31370 (3.19 e-5)	rs1012819766	VUS, PP3	33	26	HSP	Moderate axonal sensorimotor PNP	(26)
2	c.967C > T	p.(Arg323Trp)	1 /31370 (3.19 e-5)	rs1012819766	VUS, PP3	33	Childhood	HSP	Paresthesia (moderate axonal sensorimotor PNP incl. small fibers)	(26)
3	c.1082C > T	p.(Ala361Val)	7 / 247476 (2.83e-5)	rs121434444	VUS, PP3	22.1	35	HSP	Pes cavus	(46)
4	c.1082C > T	p.(Ala361Val)	7 / 247476 (2.83e-5)	rs121434444	VUS, PP3	22.1	37	PP MS	Spastic paraparesis	(47)
5	c.1086G > C	p.(Lys362Asn)	– / –	–	VUS, PM2, PP3	17.60	Unknown	HSP	Decreased pinprick and vibration sense	(48)
6	c.1238A > G	p.(Glu413Gly)	– / –	rs1399145820	VUS, PM2, PP3	24.5	35	ALS	–	(39)
7	c.1373C > T	p.(Ser458Phe)	– / –	rs1445439522	VUS, PM2	27.4	45	HSP	UL involvement (weakness shoulders, hands, atrophy, and brisk reflexes), m. SCM weakness/atrophy, m. SCM weakness and atrophy, torticollis, atrophy tongue, jerky ocular pursuit movements, ataxia, head tremor, and pes cavus	(49)
8	c.1402C > T	p.(Arg468Trp)	1 / 251048 (3.98e-6)	rs771021589	VUS, PP3	23.9	40	HSP	Ataxia, dysdiachokinesia, bradykinesia, titubation, ophthalmoparesis and dementia MRI, marked atrophy of the cerebellum and cerebral cortex (predominantly temporal and parietal)	(35)
9	c.1422A > T	p.(Gln474His)	1 / 251154 (3.98e-6)	rs1373971092	VUS, PP3	22.4	68	ALS	FTD	(39)
10	c.1624C > A	p.(His542Asn)	– / –		VUS, PM2, PP3	23.2	26	ALS	–	(37)
11	c.1673T > C	p.(Leu588Pro)	– / –	–	VUS, PM2, PP3	24.6	15	CMT2	UL: weakness LL: gait defect, weakness, pes cavus, ataxia, and tremor	(36)
12	c.1702G > A	p.(Gly568Arg)	3 / 251472 (1.19e-5)	rs763336788	VUS, PP3	22.6	34	HSP	UL involvement (hyperreflexia and Hoffman-Trömner), dysesthesia and hyperalgesia, pes cavus and hammertoes	P
13	c.1702G > A	p.(Gly568Arg)	3 / 251472 (1.19e-5)	rs763336788	VUS, PP3	22.6	18	HSP	Numbness and pain in LL, tremor, hypesthesia of UE with lowered vibration sense, deafness, and pes equines	PF
14	c.1702G > A	p.(Gly568Arg)	3 / 251472 (1.19e-5)	rs763336788	VUS, PP3	22.6	27	HSP	Numbness LL, hallux valgus, mental disability	PS
15	c.1729A > G	p.(Ser577Gly)	1 / 251404 (3.98e-6)	rs754373609	VUS, PP3	22.4	53	ALS	–	(42)
16	c.1735G > A	p.(Ala579Thr)	2 / 251376 (7.96e-6)	rs760135493	VUS, PP3	23.3	Unknown	ALS	Unknown	(44)
17	c.2024-6C > T	r.(spl?)	– / –	rs960794993	VUS, PM2	4.602	60	ALS	–	(37)
18	c.2263G > A	p.(Glu755Lys)	3 / 251394 (1.19e-5)	rs387907286	VUS, PP3	23.4	1.2	HSP	–	(33)
19	c.2263G > A	p.(Glu755Lys)	3 / 251394 (1.19e-5)	rs387907286	VUS, PP3	23.4	50 years old at examination	–	Mildly brisk reflexes UL and LL	(33)
20^c	c.2263G > A	p.(Glu755Lys)	3 / 251394 (1.19e-5)	rs387907286	VUS, PP3	23.4	14 m	HSP/ALS	UL involvement (weakness, spasticity, fasciculations, cramps) dysphagia, dysarthria, and optic atrophy	(43)
21	c.2263G > A	p.(Glu755Lys)	3 / 251394 (1.19e-5)	rs387907286	VUS, PP3	23.4	50	ALS	Onset with increased reflexes UL/LL, later fasciculation and atrophy UL and spasticity, hyperreflexia LL, dysphagia, and emotional liability	(43)
22	c.2272G > A	p.(Glu758Lys)	186 / 282810 (6.58e-4)	rs140281678	VUS, PP3	23.1	Unknown	ALS	Unknown	(44)
23^d	c.2272G > A	p.(Glu758Lys)	186 / 282810 (6.58e-4)	rs140281678	VUS, PP3	23.1	37	ALS	Memory loss, dementia	(44)
24	c.2341A > G	p.(Lys781Glu)	– / –	–	VUS, PM2, PP3	25.1	54	HSP/ALS	UL involvement (atrophy, weakness, fasciculations)	(2)
25	c.2590C > T	p.(Arg864*)	– / –	–	VUS, PM2, PP3	42	Early childhood	HSP	Sensorimotor axonal neuropathy, LL hemiatrophy, pes cavus	(50)

AA: amino acid; CMT2: Charcot Marie Tooth 2; dbSNP rsID: single nucleotide polymorphism database reference ID; FTD: frontotemporal dementia; HSP: hereditary spastic paraplegia; LL: lower limbs; m: months; m. SCM: sternocleidomastoid muscle; P: proband; PF: father; PS: sister; PNP: polyneuropathy; PP MS: primary progressive multiple sclerosis; UL: upper limbs; ACMG: the American College of Medical Genetics; VUS: variant of uncertain significance; PM2: is a moderate piece of evidence (absent from controls in Exome Sequencing Project, 1000 Genomes orf ExAC Cavaet); PP3: supporting piece of evidence (multiple lines of computational evidence support a deleterious effect on the gene or gene product).

^aFor gnomAD allele count and allele frequency gnomAD version 2.1.1 was screened, a score (-) means it was not present in the database. Number means gnomAD sample size.

^bCase 7 was also a heterozygous carrier of variants in the DCTN1 gene: c.3823C > T, p.Arg1275Cys and NEFH gene: c.1965 1988del, p.Glu658_Lys655del.

^cCase 20 was also a homozygous carrier of a variant in the ALS2 gene: c.575C > T, p.Pro192Leu, his father (case 21) and mother (healthy) shared the same heterozygous mutation in the ALS2 gene.

^dCase 23 also had a variant in the CCNF gene: p.L106V.

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