BioMed Research International / 2014 / Article / Tab 4

Research Article

Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing

Table 4

The genotype-phenotype correlation in 81 Norwegian CMT families carrying certain or likely pathogenic variants.

Gene1Nucleotide changeProtein changeFamily IDCMT typeGenotype-phenotype correlation

Certainly pathogenic
GJB1 c.688C>Tp.Arg230Cys5CMT2Family with axonal CMT and X-linked inheritance. Previously reported in [37].
HSPB1 c.380G>Tp.Arg127Leu102CMT2Novel variant, highly conserved, predicted pathogenic. Classified certainly pathogenic as previously reported CMT families had a pathogenic variant in the same codon, causing p.Arg127Trp [6]. Present in an affected patient and his affected daughter, not in his unaffected daughter.
MFN2 c.310C>Tp.Arg104Trp90CMT1Severely affected CMT1 patient with slightly decreased motor NCV, 36 m/s. Previously reported to cause early onset severe CMT2 by several [38].
SH3TC2 c.2860C>Tp.Arg954*2142, 252, 285, 295CMT1Present as homozygous in four patients from four different families with demyelinating CMT. Reported to cause CMT1 in several populations [6]. Scoliosis at variable degree was found in all cases, which is often associated with mutations in this gene. Found as heterozygous in ten unaffected family members and in five in-house controls.

Likely pathogenic
ARHGEF10 c.1013G>Cp.Arg338Thr257CMT2Novel variant, highly conserved, predicted benign but extensive change in amino acid physiochemical properties. Sporadic case with CMT2 and decreased NCV. Close proximity to another heterozygous variant (Thr332Ile) associated with decreased NCV and thin myelination [39]. Functional studies show that the Thr332Ile mutant stimulates increased actomyosin contraction, regulating cell morphology in Schwann cells [40]. Classified likely pathogenic due to similar phenotype, NCV in the same range, and close proximity to the previous reported variant.
DNM2 c.1241A>Gp.Lys414Arg9CMTTotally conserved, predicted pathogenic, situated in the dynamitin central domain. Sporadic case with unknown CMT. Not present in the unaffected daughter but in one in-house control and in one control in the ESP database; but considering the relatively high age of onset (85 years), it is uncertain whether these controls could develop neuropathy at higher age or whether the variant display reduced penetrance. Variants in DNM2 cause both axonal CMT and intermediate CMT. Situated in the same domain as another variant associated with CMT [41].
DYNC1H1 c.1700G>Ap.Arg567His231CMT2Novel variant, highly conserved situated in the dynein heavy chain, domain-1. Recently discovered as a CMT causing gene, reported to cause autosomal dominant CMT [42]. The previously reported variant (His306Arg) is situated in the same highly conserved domain as our variant and apart from some higher age of onset in our family the phenotypes correlate well. DNA was only available from one case in this family.
KIF1B c.881A>Gp.Lys294Arg123CMT2Totally conserved, predicted pathogenic, situated in the kinesin motor domain, found among one individual in the ESP database (0.008%). Situated in the same highly conserved domain as a heterozygous variant (Gln98Leu) reported in another CMT2 family [43]. Researchers have been cautious about classifying KIF1B a CMT causing gene since only one family has been reported. As functional studies of the previously reported variant have confirmed loss of motor activity and variants in other motor proteins (KIF1A, DYNC1H1, and DCTN1) also are involved in neuropathy, we consider KIF1B a possible CMT causing gene and classify our variant likely pathogenic. DNA was only available from one case in this family.
LMNA c.1930C>Tp.Arg644Cys27 
54
CMT 
CMT2
Totally conserved, predicted pathogenic. The pathogenicity of this variant has been questioned due to extreme phenotypic diversity including neuropathy and also low penetrance in affected families. But in support of its pathogenicity, found in 19 patients and not in 1000 controls (including our results), totally conserved, and studies of fibroblast carrying this variant show abnormalities of nuclear shape [44]. Found in the ESP database among 14 individuals (0.1%), but included in this database are also the affected carrying traits associated with LMNA mutations. Digenic inheritance with another variant, which is observed in three reported cases, may explain the phenotypic diversity and nonpenetrance [44]. Intriguingly, the CMT family with unknown neurophysiology carried a heterozygous variant in DCTN1, p.Arg651Trp and the sporadic CMT2 case carried a heterozygous variant in ARHGEF10, p.His733Tyr, both classified uncertain pathogenic.
POLG c.1491G>C 
c.2243G>C
p.Gln497His 
p.Trp748Ser
62CMT2p.Gln49His: highly conserved, predicted pathogenic. p.Trp748Ser: highly conserved, predicted pathogenic in one tool. Situated in the same domain. Sporadic case with CMT2. These two variants are reported to cause severe ataxic neuropathy with additional features in two Norwegian patients as compound homozygous [45]. Additionally the p.Trp748Ser variant is reported to cause neurodegenerative disorders with ataxia in three patients and dHMN in five patients as compound heterozygote [22, 46]. A patient in our clinic with simular phenotype presented with the same two variants, not seen in in-house controls or in SNP databases.
REEP1
SETX
c.524A>G 
c.3075_3076insTGA
p.*175Trpext*55 
p.Arg1026*
95CMT2REEP1: novel stop loss variant lengthening the protein by 55 residues. SETX: novel nonsense (stop codon) insertion at position 1026, shortening the protein by 1652 amino acids. Sporadic case with CMT2 and spasticity. Variants in SETX are associated with dHMN, a phenotype that overlaps with CMT2 and variants in REEP1 are associated with hereditary spastic paraplegia and in some cases dHMN [6, 47]. Thus, we assume digenic pathogenicity: the SETX variant causing CMT2 and the REEP1 variant causing spasticity.

Pathogenic variants identified among the same epidemiological population, prior to the NGS study [2, 14, 19]
GJB1 c.187G>AVal63Ile118, 256CMT1
GJB1 225delGLeu76Cysfs*883ICMT
GJB1 c.491G>AArg164Gln44CMT1
GJB1 c.658C>TArg220*398CMT2
MFN2 c.280C>TArg94Trp8CMT1
MFN2 c.281G>AArg94Gln38CMT2
MFN2 c.2119C>TArg707Trp258CMT2
MPZ c.161C>GSer54Cys39CMT1
MPZ Duplication124CMT1
PMP22 Duplication17, 51 56, 82, 136, 148, 155, 225, 309, 367CMT1
PMP22 Duplication371CMT
SOD1 c.140A>GHis46Arg1CMT2

All relevant GenBank accession and version numbers are given in Table 1.
2Present as homozygous.
CMT = unspecified Charcot-Marie-Tooth; CMT1 = demyelinating Charcot-Marie-Tooth; CMT2 = axonal Charcot-Marie-Tooth; dHMN = distal hereditary neuronopathy; ESP = the exome sequencing project; ICMT = intermediate Charcot-Marie-Tooth; NCV = nerve conduction velocity.

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