A complex homozygous mutation in ABHD12 responsible for PHARC syndrome discovered with NGS and review of the literature

Lerat, J.; Pascal, Pierre; Beauvais‐Dzugan, Hélène; Magdelaine, Corinne; Sturtz, Franck; Lia, Anne‐Sophie

doi:10.1111/jns.12216

Cited by 19 publications

(18 citation statements)

References 12 publications

(36 reference statements)

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“…2.1. Pigmentosus retinitis has been associated with PHARC syndrome [ 46 ] and with ATP6 [ 47 ] and MTMR2 gene variants [ 48 ]. Recently, a dysfunction of the endoplasmic reticulum membrane protein complex (EMC), a conserved player in the process of membrane protein biogenesis, has been reported to play a role in the pathogenesis of certain congenital diseases such as cystic fibrosis, pigmentosus retinitis, and Charcot–Marie–Tooth disease [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

et al. 2021

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(1) Background: Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations.

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Section: Discussionmentioning

confidence: 99%

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

et al. 2021

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“…Genomic DNA was extracted using standard methods (Illustra DNA Extraction kit BACC3, GEHC). Next Generation Sequencing (NGS) was performed using a 92‐genes custom panel designed for the diagnosis of CMT and associated neuropathies 7 (Ampliseq Custom [Life Technologies, Carlsbad, CA, USA]). The amplified library, which corresponds to exonic and flanking (25bp) intronic regions, was prepared using the Ion P1‐HiQ‐Template‐OT2‐200 kit (Life Technologies), sequenced on a Proton sequencer (Life Technologies), and mapped to the human reference sequence hg19/GHCh37.…”

Section: Methodsmentioning

confidence: 99%

Clinical features of homozygous FIG4‐p.Ile41Thr Charcot‐Marie‐Tooth 4J patients

Lafontaine¹,

Lia

Bourthoumieu³

et al. 2021

Ann Clin Transl Neurol

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We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4‐c.122T>C patients suffering from Charcot‐Marie‐Tooth disease type 4J (AR‐CMT‐FIG4). This syndrome usually involves compound heterozygosity associating FIG4‐c.122T>C, a hypomorphic allele coding an unstable FIG4‐p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progression, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients’ observations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR‐CMT‐FIG4‐patients might be efficient.

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“…Since this date, more than other 90 genes have been identified to be involved in this disease and in associated peripheral neuropathies [3] . Most of the detected mutations are SNVs or small indels [4] , [5] , and Structural Variants (SVs) have rarely been described [6] .…”

Section: Introductionmentioning

confidence: 99%

A mutation can hide another one: Think Structural Variants!

Miressi¹,

Faye²,

Pyromali³

et al. 2020

Computational and Structural Biotechnology Journal

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Next Generation Sequencing (NGS) using capture or amplicons strategies allows the detection of a large number of mutations increasing the rate of positive diagnosis for the patients. However, most of the detected mutations are Single Nucleotide Variants (SNVs) or small indels. Structural Variants (SVs) are often underdiagnosed in inherited genetic diseases, probably because few user-friendly tools are available for biologists or geneticists to identify them easily. We present here the diagnosis of two brothers presenting a demyelinating motor-sensitive neuropathy: a presumed homozygous c.5744_5745delAT in exon 10 of SACS gene was initially detected, while actually these patients were heterozygous for this mutation and harbored a large deletion of SACS exon 10 in the other allele. This hidden mutation has been detected thanks to the user-friendly CovCopCan software. We recommend to systematically use such a software to screen NGS data in order to detect SVs, such as Copy Number Variations, to improve diagnosis of the patients.

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A complex homozygous mutation in ABHD12 responsible for PHARC syndrome discovered with NGS and review of the literature

Cited by 19 publications

References 12 publications

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

Clinical features of homozygous FIG4‐p.Ile41Thr Charcot‐Marie‐Tooth 4J patients

A mutation can hide another one: Think Structural Variants!

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