This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified. Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing. We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed. Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.

Background/Objectives: Rhabdomyolysis is a potentially life-threatening condition characterized by acute skeletal muscle breakdown. In addition to well-described external triggers, a genetic contribution is increasingly recognized. We aimed to (I) review the genetic diagnostic approach of rhabdomyolysis, (II) evaluate the clinical characteristics indicative of a genetic susceptibility with the ‘RHABDO’ acronym, and (III) assess the predictive value of the presence RHABDO features for identifying genetic variants. Methods: In this retrospective two-center study, 122 patients underwent genetic testing for rhabdomyolysis since the introduction of whole exome sequencing (WES) in 2013. The presence of RHABDO features was compared between those with (likely) pathogenic variants and those with benign or no identified variants or variants of uncertain significance. Results: The testing methods included panel-based WES (82%), Sanger sequencing (49%), and full WES (24%), of which 52 patients (43%) underwent multiple methods. A (likely) pathogenic variant was identified in 13 patients (11%), in all of whom ≥2 RHABDO features were present. The positive predictive value for ≥2 features was 14%, while the negative predictive value was 100%. Conclusions: These results highlight the relevance of WES in further elucidating the genetic basis of rhabdomyolysis and demonstrated that RHABDO is a valuable tool for selecting patients who should undergo genetic testing.

Purpose: The expansion of specific short tandem repeats (STRs) can lead to approximately 30 different human genetic disorders. Despite extensive application of exome sequencing (ES) in routine diagnostic genetic testing, STRs are not routinely identified from these data. Methods: We assessed diagnostic utility by applying ExpansionHunter to 2,867 exomes from movement disorder patients and 35,228 other clinical exomes. Results: We identified 36 movement disorder patients with a possible aberrant STR length. Validation by PCR and/or repeat-primed PCR technologies confirmed the presence of aberrant expansion alleles for 11 (31%). For seven of these patients the genotype was compatible with the phenotypic description, and resulted in a molecular diagnosis. We subsequently tested the remainder of our diagnostic ES cohort, including over 30 clinically and genetically heterogeneous disorders. Optimized manual curation yielded 140 samples with a likely aberrant STR length. Validations confirmed 70/140 (50%) aberrant expansion alleles, of which 48 were in the pathogenic range and 22 in the premutation range. Conclusions: Our work provides guidance for the implementation of STR analysis in clinical ES. Our results show that systematic STR evaluation may increase diagnostic ES yield by 0.2%, and recommend to make STR evaluation a routine part of ES interpretation in genetic testing laboratories.