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

Abstract

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

“…In a CMT cohort of 59 families, 51 genes were included in the panel with a diagnostic yield of 25% (excluding previously diagnosed cases). In this cohort, mutations in “non‐CMT” genes were detected, and therefore a more comprehensive approach was suggested (Hoyer et al., ). Of note, in another study with a total of 33 HMN and CMT families, the importance of broader panels was underlined in case of families referred from non‐specialist centers (Lupo et al., ).…”

H46R SOD1 mutation is consistently associated with a relatively benign form of amyotrophic lateral sclerosis with slow progression

“…Therefore, it was proposed to be a unique mutation in the Asian population. However, the mutation has been reported in one USA (12), one French (13), two German (14,15) and three Norwegian (16)(17)(18) pedigrees, suggesting that it also exists in ALS patients of European descent. Although considerable inter-and intra-family variations exist regarding age of onset and disease duration, all patients with the p.H46R mutation unexceptionally had a lower limbs onset and very slow progression; the interval between the presentation of symptoms and respiratory failure usually exceeds 10 years (Table I), with the longest survival of 51 years (16).…”

“…Although considerable inter-and intra-family variations exist regarding age of onset and disease duration, all patients with the p.H46R mutation unexceptionally had a lower limbs onset and very slow progression; the interval between the presentation of symptoms and respiratory failure usually exceeds 10 years (Table I), with the longest survival of 51 years (16). Most of the patients manifested with a pure lower motor neuron disease without bulbar involvement, therefore they are easily misdiagnosed as hereditary peripheral neuropathy before a final diagnosis of ALS is made (13,(16)(17)(18). These findings indicate that the p.H46R mutation is associated with a specific phenotype, i.e.…”

Pragmatische Diagnostik hereditärer Neuropathien

“…Die Beurteilung der durch die Panel Diagnostik generierten bisher nicht beschriebenen, unklaren Varianten ist oft sehr schwierig, eine präzise Klassifikation pathologischer und nicht-pathologischer Genvarianten ist nötig, detaillierte Angaben von Klink und Familienanamnese sind notwendig zur Einschätzung einer Genotyp-Phänotyp Korrelation. Darüber hinaus machen in fast der Hälfte der Fälle die Ergebnisse eines NGS-Panel weitere umfangreiche genetische, biochemische und klinische Untersuchungen notwendig[4]. Auch kann es zu akzidentellen Ergebnissen mit z.…”

“…Auch kann es zu akzidentellen Ergebnissen mit z. B. eindeutig pathogenen Mutationen in nicht krankheitsassoziierten Genen kommen, welche die Aufklärung der Patienten zusätzlich erschwert.Auch das NGS-Panel führt derzeit in einem signifikanten Prozentsatz nicht zu einer molekulargenetischen Diagnose -je nach Studienpopulation und gewähltem Panel bleiben auch hier etwa 40 % ungeklärt[4]. Zum einen bleibt die Frage, ob der Phänotyp des untersuchten Patienten wirklich sauber charakterisiert ist, zum anderen werden auch im NGS-Panel nur die Gene, welche das Panel beinhaltet, überprüft.…”