A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation

Rocha, Maria Linda; Dittmayer, Carsten; Uruha, Akinori; Korinth, Dirk; Chaoui, Rabih; Schlembach, Dietmar; Rossi, Rainer; Pelin, Katarina; Suk, Eun Kyung; Schmid, Simone; Goebel, Hans H.; Schuelke, Markus; Stenzel, Werner; Englert, Benjamin

doi:10.1016/j.nmd.2020.11.014

Cited by 6 publications

(3 citation statements)

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“…Clinical features of AMC6 include congenital joint contractures, facial dysmorphism, skeletal anomalies, and edema with fetal hydrops. Death in infancy or fetal demise usually occurs ( Ahmed et al, 2015 ; Rocha et al, 2021 ). This couple was also found to be carriers for mutation in the INPPL1 gene, which is responsible for AR opsismodysplasia (OPSMD).…”

Section: Discussionmentioning

confidence: 99%

Identification of genetic alterations in couples and their products of conceptions from recurrent pregnancy loss in North Indian population

et al. 2023

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Background: Recurrent pregnancy loss (RPL) is one of the most common pregnancy-related complications, which can be stressful and emotionally draining for a couple. Genetic alterations, which are responsible for RPL, can be present in either of the three genomes: mother, father, or their fetuses. In addition, environmental factors interacting with these three genomes can affect germline cells. With this aim, the present study was conducted to understand the underlying etiology of RPL using Next-generation sequencing (NGS; couple exome and TRIO exomes) in combination with cytogenetic tests [karyotyping and chromosomal microarray (CMA)].Material & Methods: In present study we recruited 61 couples with RPL (history of ≥ 2 abortions) and 31 products of conceptions (POCs). For all couples karyotyping was done at the time of recruitment, followed by collection of POC samples and parental blood samples. Before processing POC samples for CMA, they were checked for maternal cell contamination (MCC) by QF-PCR. In POC samples with no pathogenic variant, TRIO exome sequencing was done. Further, in case of unavailability of POC sample, couple exome sequencing was done for RPL couples.Results: In six individuals out of 61 couples (5%), abnormality in karyotypes was detected. Among 116 normal karyotypes, there were 11 heteromorphisms (9.5%), for which the couples had to be counselled and reassured. Out of the 31 POCs, 10 were excluded because of MCC (around 30%) and one had major aneuploidy. CMA in POCs identified pathogenic copy number variations (CNVs) in 25% of cases (5/20) and variant of unknown significance (VUS) in 20% of cases (4/20). Autosomal trisomy was the most frequent chromosomal abnormality diagnosed. NGS was performed to establish single-gene causes of RPL. Couple exome sequencing was performed in 20 couples, and 14 were found to be carriers for autosomal recessive conditions. A total of 50 potential disease-causing variants in 40 genes were identified in 33 of 40 individuals (82.5%). Putative causative variants were identified in 37.5% of the TRIO cases (3/8). Mutations in few important genes (SRP54, ERBB4, NEB, ALMS, ALAD, MTHFR, F5, and APOE), which are involved in vital pathways, early embryonic development, and fetal demise, were identified in the POCs.Conclusion: It enhances our understanding of prenatal phenotypes of many Mendelian disorders. These mutated genes may play an auxiliary role in the development of treatment strategies for RPL. There was no correlation of the number of abortions with etiological yield of any technique to detect the cause of RPL. This study shows the utilization of combination of techniques in improving our understanding of the cause of early embryonic lethality in humans.

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Section: Discussionmentioning

confidence: 99%

Identification of genetic alterations in couples and their products of conceptions from recurrent pregnancy loss in North Indian population

et al. 2023

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“…In a review of 10 fetuses with NM, polyhydramnios and decreased fetal movement were commonly detected, ranging from week 13 to the third trimester. Club feet were often observed around week 20 ( Yonath et al, 2012 ; Bohm et al, 2013 ; Rocha et al, 2021 ). After birth, arthrogryposis, club foot, undescended testes, respiratory failure, and muscle weakness were frequently observed.…”

Section: Discussionmentioning

confidence: 99%

Case report: identification of one frameshift variant and two in cis non-canonical splice variants of NEB gene in prenatal arthrogryposis

Liu,

Xu,

et al. 2023

Front. Genet.

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NEB mutation is associated with congenital nemaline myopathies. Here, we report a family with recurrent prenatal arthrogryposis. Trio whole exome sequencing (WES) disclosed three novel NEB (NM_001271208.2) variants including one paternal frameshift c.19049_19050delCA (p.Thr6350Argfs*14) and two double maternal variants in cis c. [24871G>T;24871-10C>G] (p. [Val8291Phe;?]). They are evaluated as “likely pathogenic (LP)”, “variant of uncertain of significance (VUS)”, and “VUS”, respectively. After further prediction, the c.24871G>T, c.24871-10C>G, and c.[24871G>T;24871-10C>G] were respectively genetically engineered into the three plasmids. Compared with their wild-type counterparts, the three plasmids all produced truncated transcripts, and also a significant proportion of the full-length transcripts, which allowed us to reclassify NEB c.24871G>T and c.24871-10C>G variants as LP. As far as we know, this is the first case carrying NEB allele-specific function of partial loss. This result helped the couple make informed reproductive choices and opt for assisted reproduction for future pregnancies. This study also increased awareness to the phenotype of prenatal nemaline myopathy and expanded the variant spectrum of NEB.

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“…Autosomal recessive mutations in NEB encoding nebulin were reported to cause NM in 1999 [25]. Romero et al first reported a case with core-rod myopathy caused by NEB gene mutation that showed generalized hypotonia and required immediate intubation and resuscitation at birth [26] [30]. Previous study reported a NEB-related adult NM patient presenting slowly progressive distal myopathy with respiratory and heart failure.…”

Section: Discussionmentioning

confidence: 99%

A Childhood-Onset Nemaline Myopathy Caused by Novel Compound Heterozygote Variants in the Nebulin Gene

Xu,

Wu,

et al. 2023

austinjclincaserep

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Congenital myopathies are clinically and genetically heterogeneous disorders, which often remain genetically undiagnosed for many years. Here we present a 20-year-old patient showing gradually deteriorated proximal muscle weakness and rod-shaped structures found in muscle fibers was suspected of having nemaline myopathy. Whole-exome sequencing and subsequent Sanger sequence analysis for the patient revealed a pathogenic mutation in NEB gene c.21522+3 (IVS 144) A>G and c.23722 (exon 165) A>T. Based on genetic analyses, we identified two novel, compound- heterozygous variants in the NEB gene, which cause a childhood- onset nemaline myopathy.

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A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation

Cited by 6 publications

References 35 publications

Identification of genetic alterations in couples and their products of conceptions from recurrent pregnancy loss in North Indian population

Identification of genetic alterations in couples and their products of conceptions from recurrent pregnancy loss in North Indian population

Case report: identification of one frameshift variant and two in cis non-canonical splice variants of NEB gene in prenatal arthrogryposis

A Childhood-Onset Nemaline Myopathy Caused by Novel Compound Heterozygote Variants in the Nebulin Gene

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