Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies

Chen, Zhongbo ORCID: 0000-0001-6668-7202, Maroofian, Reza, Basak, A. Nazli, Shingavi, Leena, Karakaya, Mert, Efthymiou, Stephanie, Gustavsson, Emil K., Meier, Leyla, Polavarapu, Kiran, Vengalil, Seena, Preethish-Kumar, Veeramani, Nandeesh, Bevinahalli N., Gunes, Nalan Gokce, Akan, Onur, Candan, Fatma, Schrank, Bertold, Zuchner, Stephan, Murphy, David, Kapoor, Mahima, Ryten, Mina, Wirth, Brunhilde, Reilly, Mary M., Nalini, Atchayaram, Houlden, Henry and Sarraf, Payam . Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies. Eur. J. Neurol.. HOBOKEN: WILEY. ISSN 1468-1331

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DOI:10.1111/ene.14649

Abstract

Background and purpose Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease. Methods We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature. Results We found that patients presented with variable disease severity at different ages of onset (8-25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5-associated neuropathies, which are phenotypically spinal muscular atrophy (SMA) or intermediate Charcot-Marie-Tooth disease. Conclusions PLEKHG5-associated neuropathies should be considered as an important differential in non-5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5-associated diseases.

Item Type:

Journal Article

Creators:

Creators	Email	ORCID	ORCID Put Code
Chen, Zhongbo	UNSPECIFIED	orcid.org/0000-0001-6668-7202	UNSPECIFIED
Maroofian, Reza	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Basak, A. Nazli	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Shingavi, Leena	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Karakaya, Mert	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Efthymiou, Stephanie	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Gustavsson, Emil K.	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Meier, Leyla	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Polavarapu, Kiran	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Vengalil, Seena	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Preethish-Kumar, Veeramani	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Nandeesh, Bevinahalli N.	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Gunes, Nalan Gokce	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Akan, Onur	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Candan, Fatma	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Schrank, Bertold	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Zuchner, Stephan	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Murphy, David	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Kapoor, Mahima	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Ryten, Mina	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Wirth, Brunhilde	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Reilly, Mary M.	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Nalini, Atchayaram	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Houlden, Henry	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Sarraf, Payam	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED