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Confirmation of the GNB4 Gene As Causal for Charcot–Marie–Tooth

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Confirmation of the GNB4 Gene As Causal for Charcot–Marie–Tooth Available online at www.sciencedirect.com ScienceDirect Neuromuscular Disorders 27 (2017) 57–60 www.elsevier.com/locate/nmd Case report Confirmation of the GNB4 gene as causal for Charcot–Marie–Tooth disease by a novel de novo mutation in a Czech patient Petra Laššuthová a,*, Dana Šafka Brožková a, Jana Neupauerová a, Marcela Kru˚tová a, Radim Mazanec b, Pavel Seeman a a Department of Paediatric Neurology, DNA Lab, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic b Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic Received 27 June 2016; received in revised form 9 September 2016; accepted 12 September 2016 Abstract The association of GNB4 with Charcot–Marie–Tooth (CMT) has recently been described in a publication by Soong et al. (Soong, et al., 2013). Here we present a patient with CMT in whom whole exome sequencing identified the mutation p.Lys57Glu in the GNB4 gene (NM_021629.3:c.169A>G). The patient, now 41 years old, is a sporadic case in the family.At the age of 35 he presented with severe disability (CMT neuropathy score 29), profound muscle atrophies, pes cavus and scoliosis. Previously, the patient was tested for PMP22 duplications/deletions and later also with 64 CMT gene panel, with no causal variant found. Subsequently, whole exome sequencing was performed. The p.Lys57Glu in the GNB4 gene was identified as the most probable causal variant, the mutation is not present in the patient’s parents, neither in his unaffected sister, therefore we assume that the mutation arose de novo. Taken together, these findings support the causal and pathogenic character of the variant. Our report provides important evidence that GNB4 should become an established CMT gene and our findings confirm the original publication by Soong et al. (2013). © 2016 Elsevier B.V.All rights reserved. Keywords: Charcot–Marie–Tooth disease; De novo; Whole exome sequencing; GNB4 1. Introduction The utility of WES in novel genes discoveries is well established. However, in multiple cases, finding a patient from Charcot–Marie–Tooth (CMT) disease is a heterogeneous an independent study to support the causal role of mutations in group of disorders, with neuropathy being the sole or primary these novel genes is difficult. part of the disease [1]. Variants in many genes have already been Here we present a patient in whom whole exome sequencing associated with the phenotype (currently more than 90 causative identified a pathogenic variant in the GNB4 gene. This is only genes). the third patient worldwide that confirms the causality of this Molecular genetic diagnosis of CMT is challenging. Variants novel gene. The association of GNB4 mutations with Charcot– in the four most common genes (PMP22, MPZ, MFN2 and Marie–Tooth (CMT) has only been recently described. The GJB1) account for almost 90% of positive cases. Achieving a original publication describes two mutations in two unrelated genetic diagnosis for the remaining 10% of patients with Chinese families, one with autosomal dominant inheritance, the clinically well stated CMT is very complicated. Targeted gene other a sporadic case due to a de novo mutation [2]. No further panel analysis is the method of choice, with an approximate reports have been published so far. success rate of 25%. If this approach is not able to identify the Our results support the causal role of GNB4 gene variants in variant that could possibly explain the cause of the disease, Charcot–Marie–Tooth disease. whole exome sequencing (WES) with various evaluation models (dominant; de novo or recessive) is the next logical step. 2. Case report The patient, now 41 years old, is a sporadic case with CMT1 in the family. His parents and his sister do not show any signs of peripheral neuropathy, although they were not neurologically, * Corresponding author. Department of Paediatric Neurology, DNA Lab, 2nd Faculty of Medicine, Charles University in Prague and University Hospital nor electrophysiologically tested. He has no children. Motol, Prague, Czech Republic. Fax: +420 224 435 820. The first signs of disease occurred during early school age. E-mail address: [email protected] (P. Laššuthová). These were mainly frequent falls and difficulties while running. http://dx.doi.org/10.1016/j.nmd.2016.09.010 0960-8966/© 2016 Elsevier B.V.All rights reserved. 58 P. Laššuthová et al./Neuromuscular Disorders 27 (2017) 57–60 Distal muscle weakness and atrophies in the lower limbs were dorsiflexion/plantar flexion 3/5). Sensory loss in a stocking observed before the age of 10 years. During the growth spurt in distribution was noted. He was unable to distinguish sharp/blunt puberty his symptoms worsened, muscle wasting became stimuli distally up to the knee and vibration sense was prominent (in the legs distally below the knee and also of small diminished at the feet. Gait without support was preserved but muscles in the hands). The patient has suffered tremors of the the patient was unable to walk on his heels. There was scoliosis. fingers of both hands since the age of 16 years. At the age of The Charcot–Marie–Tooth Neuropathy Score was 20. Clinical 31 years he underwent orthopedic surgery for foot deformities. examination at the age of 35 years showed muscle atrophy of Further progression occurred in his thirties, muscles atrophies the forearm up to the elbow. Hypothenar muscle wasting was in the upper limbs were noticed and thoracic spine scoliosis more prominent than thenar muscle wasting. C5-C8 deep tendon began to develop (Fig. 1). Clinical examination at the age of 30 reflexes were absent. Muscle was severely diminished in the years showed atrophy of the small hand muscles and diminished hands and finger tremor was noted. Shoulder abduction and deep tendon reflexes. Muscle strength (MRC scale) was reduced elbow flexion/extension strength was 4/5; wrist extension/ both proximally and distally in the upper limbs (shoulder flexion was 3/5. Hand grip strength bilaterally was 25 kPa. abduction, elbow flexion/extension 4/5, wrist extension/flexion The patient underwent orthopedic surgery twice at the age 31 3/5, finger abduction 3/5). Hand grip was 50 and 52 kPa on (Achilles tendon shortenings). Deep tendon reflexes in the the left and right side, respectively. Sensory testing was legs were absent. Sensory testing revealed tactile hypoesthesia normal in the upper limbs. In the lower limbs, severe distal distally up to the knee, bilaterally. Vibration sense was amyotrophy was present whereas more proximally atrophy was severely diminished at the toe tips, metatarsal phalangeal milder. There was foot deformity with calluses and Achilles joints and tibial tuberosity and absent at the fingers. Gait tendon shortening (105°). Deep tendon reflexes were absent. was possible only with support (2 canes). The Charcot–Marie– Muscle weakness was observed both proximally and distally Tooth Neuropathy Score was 29. Nerve conduction studies (hip flexion/extension 4/5, knee flexion/extension 4/5; foot revealed primary demyelinatingneuropathy with secondary Fig. 1. Patient at the age of 35 years. P. Laššuthová et al./Neuromuscular Disorders 27 (2017) 57–60 59 axonal loss. Nerve conduction studies were performed at the 3. Discussion age of 30 years: Motor nerve conduction velocities: median Here we present the first report following the original report, nerve, 12 m/s; peroneal nerve, 4 m/s; tibial nerve, 4 m/s. for association of GNB4 mutations and Charcot–Marie–Tooth Sensory nerve conduction velocities: ulnar and sural nerves: disease. not recordable. Compound muscle action potential (CMAP): Clinically, patients described in the original paper presented median nerve, 1.8 mV; peroneal nerve, 0.2 mV; tibial nerve, with various clinical severity from asymptomatic to wheelchair 0.1 mV. EMG showed spontaneous muscle fiber activity at bound. The authors reported intermediate CMT, however, the rest in the left tibialis anterior muscle. (This is evidence of girl with p.Lys89Glu mutation presented with demyelinating a primary demyelinating neuropathy with secondary axonal neuropathy with axonal loss. The same was observed for our loss and ongoing denervation). patient. The patient entered our CMT diagnostic scheme 15 years The mutation p.Lys57Glu occurred at the evolutionary ago at the age of 25 years. conserved residue (based on 15 ortholog alignments, according Previously, the patient was tested for PMP22 duplication/ to Ensembl Compara database – http://www.ensembl.org/info/ deletion in 2001 and because of the high suspicion of a genetic genome/compara/index.html, accessed 16-05-2016). cause of his neuropathy, Sanger sequencing of all coding The variant was evaluated in adherence to ACMG standards exons of genes relevant to his phenotype was later also [3]. Accordingly, the variant might be characterized as performed: MPZ, PMP22, GJB1, SH3TC2, FBLN5, HK1, pathogenic (1 strong, 2 moderate and 2 supportive criteria), as GDAP1. Afterwards, in 2013 targeted massively parallel summarized in Table 1 [4–6]. sequencing of a panel of all 64 genes, mutations of which were Although the parents and sister of the proband were not associated with inherited peripheral neuropathies at that time, neurologically, nor electrophysiologically tested, we assume was conducted (GNB4 gene not included). No significant they are without signs of the peripheral neuropathy. The first variant that could explain the cause of CMT in this patient was signs of the disease occurred in our proband at the age of found. Therefore, we sought to determine the genetic basis for 10 years. The parents, now 72 and 71 years old, describe CMT in this patient using WES. This was done with Agilent themselves as being healthy. His sister is now 42 years old. SureSelect Human All Exon V5 kitSanger seq (Agilent, Santa None of them report any complaints.
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