Biallelic mutation of<i>CLRN2</i>causes non-syndromic hearing loss in humans

Vona, Barbara; Mazaheri, Neda; Lin, Sheng‐Jia; Dunbar, Lucy A; Maroofian, Reza; Azaiez, Héla; Booth, Kevin T.; Vitry, Sandrine; Rad, Abolfazl; Varshney, Pratishtha; Fowler, Ben; Alagramam, Kumar N.; Murphy, David; Shariati, Gholamreza; Sedaghat, Alireza; Houlden, Henry; Kumar, Shruthi Vijay; Smith, Richard J.; Haaf, Thomas; El-Amraoui, Aziz; Bowl, Michael R.; Varshney, Gaurav K.; Galehdari, Hamid

doi:10.1101/2020.07.29.222828

Cited by 3 publications

(4 citation statements)

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“…Data processing, sequence alignment to GRCh37/GRCh38, and variant filtering and prioritization by allele frequency, predicted functional impact, and inheritance models were performed as previously reported. [22][23][24][25][26][27][28] WES data output is summarized in Table S1. Co-segregation analysis was performed by Sanger sequencing in all but family 7.…”

Section: Genomic Analysesmentioning

confidence: 99%

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Lin

Niceta

Muto

et al. 2021

The American Journal of Human Genetics

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Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that biallelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal anomalies, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3 -/mice showed craniofacial and dental defects, reduced body size and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.

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Section: Genomic Analysesmentioning

confidence: 99%

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Lin

Niceta

Muto

et al. 2021

The American Journal of Human Genetics

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“…Computational analysis of the c.174G>C variant was performed as previously described 15 . To assess the predicted splicing impact of the c.174G>C (p.Gln58His) variant in Patients 1 and 2, an in vitro splicing assay was performed with minor modifications 16 …”

Section: Methodsmentioning

confidence: 99%

“…Fluorescence-activated cell sorting analysis to assess for reduction in cell-surface expression of GPI-APs was done for Patient 6 and performed as previously described. 15 3 | RESULTS…”

Section: Flow Cytometry Analysesmentioning

confidence: 99%

“…This is consistent with the previously reported case series that showed biallelic variants in PIGS lead to reduced amounts of GPI-AP at the cell surface. 15,16 Due to the country of origin of the two patients still alive and the limited clinical facilities, we could not replicate the flow cytometric analysis in additional individuals.…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

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Expanding the phenotype of PIGS‐associated early onset epileptic developmental encephalopathy

et al. 2021

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The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol‐anchored protein (GPI‐AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI‐APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine‐responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS‐related disorder. Further delineation of the molecular spectrum of PIGS‐related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.

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Non-syndromic hearing loss: clinical and diagnostic challenges

Vona

Doll²,

Hofrichter³

et al. 2020

Medizinische Genetik

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Hereditary hearing loss is clinically and genetically heterogeneous. There are presently over 120 genes that have been associated with non-syndromic hearing loss and many more that are associated with syndromic forms. Despite an increasing number of genes that have been implemented into routine molecular genetic diagnostic testing, the diagnostic yield from European patient cohorts with hereditary hearing loss remains around the 50 % mark. This attests to the many gaps of knowledge the field is currently working toward resolving. It can be expected that many more genes await identification. However, it can also be expected, for example, that the mutational signatures of the known genes are still unclear, especially variants in non-coding or regulatory regions influencing gene expression. This review summarizes several challenges in the clinical and diagnostic setting for hereditary hearing loss with emphasis on syndromes that mimic non-syndromic forms of hearing loss in young children and other factors that heavily influence diagnostic rates. A molecular genetic diagnosis for patients with hearing loss opens several additional avenues, such as patient tailored selection of the best currently available treatment modalities, an understanding of the prognosis, and supporting family planning decisions. In the near future, a genetic diagnosis may enable patients to engage in preclinical trials for the development of therapeutics.

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Biallelic mutation ofCLRN2causes non-syndromic hearing loss in humans

Cited by 3 publications

References 62 publications

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Expanding the phenotype of PIGS‐associated early onset epileptic developmental encephalopathy

Non-syndromic hearing loss: clinical and diagnostic challenges

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