Table 2.

Variants identified by whole exome and whole genome sequencing in probands with genetic neuropathies.

Family ID	Sex	Anc.	AAO	Clinical features	Gene variant zygosity ClinVar accession(s)	Disease (MONDO ID) inheritance	ACMG classification with evidence codes
Solved cases
fam_006a	F	SAC	10	HMN plus, hyperreflexia	MFN2 NP_055689.1:p.Thr206Ala het SCV003930375	CMT axonal type 2A2 (MONDO:0012231) AD	LP (PP3, PM1, PM2_supp, PM5)
fam_081a	M	SAC	24	HMN; Optic neuropathy	MFN2 NP_055689.1:p.Arg259Cys het SCV003930377	CMT axonal type 2A2 (MONDO:0012231) AD	P (PP3_str, PM1, PM2_supp, PM5, PS4)
fam_083a	F	SAC	10	CMT2; pyramidal signs	MFN2 NP_055689.1:p.Arg280His het SCV003930380	CMT axonal type 2A2 (MONDO:0012231) AD	P (PP1_str, PP3_mod, PM1, PM2_supp, PM5, PS3_supp, PS4)
ICGNMD_18b	M	SAC	14	CMT2	MORC2 NP_001290185.1:p.Arg252Trp het SCV003930346	CMT axonal type 2Z (MONDO:0014736) AD	P (PP1_str, PP2, PP3, PM1, PM2_supp PS3_supp, PS4)
ICGNMD_16b	F	B	10	CMT2	ATP1A1 NP_000692.2:p.Ile592Thr het SCV003852622	CMT axonal type 2DD (MONDO:0054833) AD	LP (PP1_supp, PP2, PP3_mod, PM1, PM2_supp, PS3_supp, PS4_supp)
ICGNMD_59b	F	W	11	CMT2 + median neuropathy	GJB1 NP_000157.1:p.Arg22Ter het SCV003930347	CMT X-linked dominant 1 (MONDO:0010549) AD	P (PP1, PM1, PM2_supp, PS4, PVS1)
ICGNMD_17b	F	W	20	HMN plus	ADPRS NP_060295.1:p.Val335Gly hom SCV003930343	Neurodegeneration, childhood-onset, stress-induced, variable ataxia and seizures (MONDO:0100095) AR	LP (PP1_str, PM2_supp, PM3, PS3_supp)
ICGNMD_4b	F	SAC	3	Ataxic neuropathy plus	ATM NP_000042.3:p.Thr1743IIe hom SCV003930348	Ataxia telangiectasia (MONDO:0008840) AR	LP (PP3_mod, PM2_supp, PM3_str, PS3_supp)
Probably solved cases
ICGNMD_15b	F	SAC	<10	CMT2	GAN NP_071324.1:p.Gln94Ter and NP_071324.1:p.Pro315Leu c/het SCV003930344 SCV003930345	Giant axonal neuropathy (MONDO:0000128) AR	VUS (PM2_supp, PVS1) and VUS (PM2_supp, PS4_supp)
ICGNMD_6b	M	W	45	CMT mixed	MPZ NP_000521.2:p.Glu71Gly het SCV003852624	CMT2I (MONDO:0011889) AD	VUS (PM1, PM2_supp, BP4)
Unsolved cases with variants of uncertain significance
fam_007a ICGNMD_7a,b ICGNMD_9a,b	M F F	B B B	5 13 20	CMT2	MPV17 NP_002428.1:p.Gln36Ter and NP_002428.1:p.Arg125Trp c/het SCV003930386 SCV003930388	CMT axonal type 2EE (MONDO:0032728) AR	VUS (PM2_supp, PVS1 not met*) and VUS (PM2_supp, PP3)

M, male; F, female; W, White or European-genetic ancestry; SAC, South African Coloured; B, Black African; I, Indian-ancestry; Anc, ancestry; AAO, age at onset (years).

^aRefers to whole genome sequencing.

^bRefers to whole exome sequencing.

Het, heterozygous; hom, homozygous; c/het, compound heterozygous, although such variants were not confirmed in trans; AD, autosomal dominant; AR, autosomal recessive; VUS, variant of uncertain significance; LP, likely pathogenic; P, pathogenic; sup, supporting; mod, moderate; str, strong.

Novel variants (not previously implicated in disease) are shown in bold. CMT, Charcot-Marie-Tooth. HMN plus refers to clinical sensory impairment but normal sensory nerve action potentials on electrophysiology. CMT2 refers to an axonal sensorimotor neuropathy (nerve conduction velocities (CVs) >45m/s) (20). CMT mixed refers to an overall axonal pattern, although some nerves showed CVs <38 m/s. The median neuropathy refers to delayed distal latency and a conduction block in the forearm (>20% drop between proximal and distal motor amplitudes).

^*PVS1 not assigned as loss of gene function is not an established pathogenic mechanism for MPV17-related CMT2EE (the majority of MPV17 variants associated with CMT2EE are homozygous missense variants while the single reported homozygous non-frameshift deletion, p.Asp126_Tyr136del, removes <10% of the MPV17 protein).