Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans

Seidahmed, Mohammed Zain; Al-Kindi, Adila; Alsaif, Hessa S.; Miqdad, Abeer M.; Alabbad, Nasser S.; Alfifi, Abdallah; Abdelbasit, Omer B.; Al-Hussein, Khalid; Alsamadi, Abdulmohsen; Ibrahim, Niema; Futaisi, Amna Al; Al‐Maawali, Almundher; Alkuraya, Fowzan S.

doi:10.1007/s00439-020-02117-7

Cited by 15 publications

(12 citation statements)

References 15 publications

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“…The combination of arthrogryposis, callosal abnormalities, and ventriculomegaly observed in the USP14‐related MCC phenotype we report, is also reminiscent of the constellation of features seen in the recently described Zain syndrome due to biallelic SYCL2 variants 24 . Our cases can be distinguished from this entity with arthrogryposis limited to the distal limbs, and absence of joint dislocations and fractures.…”

Section: Discussionsupporting

confidence: 81%

“…The combination of arthrogryposis, callosal abnormalities, and ventriculomegaly observed in the USP14-related MCC phenotype we report, is also reminiscent of the constellation of features seen in the recently described Zain syndrome due to biallelic SYCL2 variants. 24 Our cases can be distinguished from this entity with arthrogryposis limited to the distal limbs, and absence of joint dislocations and frac- caused by biallelic KIAA1109 variants (MIM #617822). [25][26][27][28] Because none of our cases had undergone an autopsy, we are not acquainted with the histopathological distinction of these entities with the USP14 phenotype described here.…”

Section: Discussionmentioning

confidence: 76%

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Functional loss of ubiquitin‐specific protease 14 may lead to a novel distal arthrogryposis phenotype

et al. 2022

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Multiple congenital contractures (MCC) comprise a number of rare, non‐progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin‐specific protease 14 (USP14) encodes a major proteasome‐associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14‐deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4‐bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT‐qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense‐mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 76%

Functional loss of ubiquitin‐specific protease 14 may lead to a novel distal arthrogryposis phenotype

et al. 2022

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“…We used two variants from Arab patients that were published in peer-reviewed journals: NM_017988.4:c.106C>T, which a protein terminating variant with very low AF (< 1%) reported in a Saudi family; the parents are first cousins, diagnosed with arthrogryposis multiplex congenital (AMC); and NM_000933.3:c.1862G>A. This is a novel (not found on gnomAD) missense alteration that was reported in an Egyptian family with a history of auriculocondylar syndrome (ARCND) with highly variable clinical phenotypes [31], [32]. The two variants were inserted into the two research WES files.…”

Section: Clinical Testingmentioning

confidence: 92%

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

Sobahy

Motwalli

Alazmi

2022

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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Background & Objective: Genomic medicine stands to be revolutionized by understanding single nucleotide variants (SNVs) and their expression in single-gene disorders (Mendelian diseases). Computational tools can play a vital role in the exploration of such variations and their pathogenicity. Consequently, we developed the ensemble prediction tool AllelePred to identify deleterious SNVs and disease causative genes. Results: The model utilizes different population genetics backgrounds and restricted criteria for features selection to help generate high accuracy results. In comparison to other tools, such as Eigen, PROVEAN, and fathmm-MKL our classifier achieves higher accuracy (98%), precision (96%), F1 score (93%), and coverage (100%) for different types of coding variants. The new method was also compared against a bioinformatics analytical workflow, which uses gnomAD overall AFs (less than 1%) and CADD (scaled C-score of at least 15). Furthermore, this research highlights the stature of genetic variant sharing and curation. We accumulated a list of highly probable deleterious variants and recommended further experimental validation before medical diagnostic usage. Conclusions: The ensemble prediction tool AllelePred enables increased accuracy in recognizing deleterious SNVs and the genetic determinants in real clinical data.

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“…We used two variants (from Arab patients) that were published in peer-reviewed journals: NM_017988.4:c.106C>T, which a protein terminating variant with very low AF (< 1%) reported in a Saudi family; the parents are first cousins, diagnosed with arthrogryposis multiplex congenita (AMC); and NM_000933.3:c.1862G>A. This is a rare (not found on gnomAD) missense alteration that was reported in an Egyptian family with history of auriculocondylar syndrome (ARCND) with highly variable clinical phenotypes [26], [27]. The two variants were inserted into the two research WES files.…”

Section: Clinical Testingmentioning

confidence: 94%

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

Sobahy¹,

Motwalli²

2021

Preprint

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Genomic medicine stands to be revolutionized through the understanding of single nucleotide variants (SNVs) and their expression in single-gene disorders (mendelian diseases). Computational tools can play a vital role in the exploration of such variations and their pathogenicity. Consequently, we developed the ensemble prediction tool AllelePred to identify deleterious SNVs and disease causative genes. In comparison to other tools, our classifier achieves higher accuracy, precision, F1 score, and coverage for different types of coding variants. Furthermore, this research analyzes and structures 168,945 broad spectrum genetic variants from the genomes of the Saudi population to denote the accuracy of the model. When compared, AllelePred was able to structure the unlabeled Saudi genetic variants of the dataset to mimic the data characteristics of the known labeled data. On this basis, we accumulated a list of highly probable deleterious variants that we recommend for further experimental validation prior to medical diagnostic usage.<br>

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Recessive mutations in SCYL2 cause a novel syndromic form of arthrogryposis in humans

Cited by 15 publications

References 15 publications

Functional loss of ubiquitin‐specific protease 14 may lead to a novel distal arthrogryposis phenotype

Functional loss of ubiquitin‐specific protease 14 may lead to a novel distal arthrogryposis phenotype

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

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