Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia

Abstract Background Osteocraniostenosis (OCS) is a rare genetic disorder characterised by premature closure of cranial sutures, gracile bones and perinatal lethality. Previously, diagnosis has only been possible postnatally on clinical and radiological features. This study describes the first prenatal diagnosis of OCS. Case presentation In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. This mutation had previously been detected in two cases and was lethal in both perinatally. This established the diagnosis, a clear prognosis and allowed informed parental choice regarding ongoing pregnancy management. Conclusions This case report supports the use of targeted WES prenatally to confirm the underlying cause and prognosis of sonographically suspected abnormalities.

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Decision letter for "Whole exome sequencing revealed a nonsense mutation in STKLD1 causing non‐syndromic pre‐axial polydactyly type A affecting only upper limb"

10.1111/cge.13547/v3/decision1 ◽

2019 ◽

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Upper Limb ◽

Nonsense Mutation ◽

Type A ◽

Whole Exome

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Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing

PLoS ONE ◽

10.1371/journal.pone.0156981 ◽

2016 ◽

Vol 11 (6) ◽

pp. e0156981 ◽

Cited By ~ 14

Author(s):

Xiaoru Xia ◽

Caijun Dai ◽

Xiaochun Zhu ◽

Qiumei Liao ◽

Xu Luo ◽

...

Keyword(s):

Rare Disease ◽

Exome Sequencing ◽

Nonsense Mutation

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A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

10.1101/2020.11.23.394098 ◽

2020 ◽

Author(s):

Harvey Perez ◽

May F. Abdallah ◽

Jose I. Chavira ◽

Martin T. Egeland ◽

Karen L. Vo ◽

...

Keyword(s):

Mouse Model ◽

Ataxia Telangiectasia ◽

Nonsense Mutation ◽

Genome Stability ◽

Cerebellar Atrophy ◽

Genotoxic Stress ◽

Purkinje Neuron ◽

Cerebellar Dysfunction ◽

Severe Ataxia ◽

Human Disorder

AbstractAtaxia Telangiectasia (A-T) is caused by null mutations in the genome stability gene, ATM (A-T mutated). In mice, similar null mutations do not replicate A-T’s characteristic severe ataxia with associated cerebellar dysfunction and atrophy. By increasing genotoxic stress, through the insertion of null mutations in the Atm (nonsense) and related Aptx (knockout) genes, we have generated a novel A-T mouse that first develops mild ataxia, associated with abnormal Purkinje neuron (PN) activity and decreased size, progressing to severe ataxia correlated with further reduced PN activity as well as PN loss and overall cerebellar atrophy. These mice also exhibit high incidences of cancer and immune abnormalities that are all hallmarks of the human disorder. Enabled by the insertion of a clinically relevant nonsense mutation in Atm, we demonstrate that small molecule readthrough (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

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A Novel Nonsense Mutation in TRIP4 Gene Causes Severe Muscular Weakness with Respiratory Failure and Cardiomyopathy but without Skin, Joint, and/or Bone Abnormalities

Neuropediatrics ◽

10.1055/s-0037-1602929 ◽

2017 ◽

Vol 48 (S 01) ◽

pp. S1-S45

Author(s):

J. Johannsen ◽

J. Heinemeyer ◽

M. Hempel ◽

D. Lessel ◽

S. Mueller-Stoever ◽

...

Keyword(s):

Respiratory Failure ◽

Nonsense Mutation ◽

Muscular Weakness ◽

Bone Abnormalities

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First Infertile Case with CSTF2TGene Mutation

Molecular Syndromology ◽

10.1159/000509686 ◽

2020 ◽

Vol 11 (4) ◽

pp. 228-231 ◽

Cited By ~ 1

Author(s):

Ozlem Gorukmez ◽

Orhan Gorukmez

Keyword(s):

Male Infertility ◽

Exome Sequencing ◽

Gene Mutation ◽

Nonsense Mutation ◽

Genetic Factors ◽

Male Mice ◽

Infertile Patient ◽

Infertile Men ◽

Clinical Exome Sequencing ◽

Homozygous Nonsense Mutation

Male infertility is multifactorial and presents with heterogeneous phenotypic features. Genetic factors are responsible for up to 15% of the male infertility cases. Loss of the Cstf2t gene in male mice results in infertility. No disease-associated mutations have been described for this gene in infertile men. Here, we report a patient diagnosed with infertility in whom a homozygous nonsense mutation in the CSTF2T gene was detected by clinical exome sequencing. This case is the first description of an infertile patient who has a homozygous CSTF2T mutation.

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