Palmoplantar keratoderma and Charcot-Marie-Tooth disease: combination of two independent genetic diseases? Identification of two point mutations in the MPZ
 and KRT1
 genes by whole-exome sequencing

AbstractOver 94 million domestic cats are susceptible to cancers and other common and rare diseases. Whole exome sequencing (WES) is a proven strategy to study these disease-causing variants. Presented is a 35.7 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. Whole exome sequencing was conducted on 41 cats with known and unknown genetic diseases and traits, of which ten cats had matching whole genome sequence (WGS) data available, used to validate WES performance. At 80 × mean exome depth of coverage, 96.4% of on-target base coverage had a sequencing depth > 20-fold, while over 98% of single nucleotide variants (SNVs) identified by WGS were also identified by WES. Platform-specific SNVs were restricted to sex chromosomes and a small number of olfactory receptor genes. Within the 41 cats, we identified 31 previously known causal variants and discovered new gene candidate variants, including novel missense variance for polycystic kidney disease and atrichia in the Peterbald cat. These results show the utility of WES to identify novel gene candidate alleles for diseases and traits for the first time in a feline model.

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Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing

European Journal of Dermatology ◽

10.1684/ejd.2021.4017 ◽

2021 ◽

Vol 31 (2) ◽

pp. 264-265

Author(s):

So Takeuchi ◽

Takuya Takeichi ◽

Yasutoshi Ito ◽

Kana Tanahashi ◽

Yoshinao Muro ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Causative Mutation ◽

Palmoplantar Keratoderma ◽

Whole Exome

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PCNT point mutations and familial intracranial aneurysms

Neurology ◽

10.1212/wnl.0000000000006614 ◽

2018 ◽

Vol 91 (23) ◽

pp. e2170-e2181 ◽

Cited By ~ 6

Author(s):

Oswaldo Lorenzo-Betancor ◽

Patrick R. Blackburn ◽

Emily Edwards ◽

Rocío Vázquez-do-Campo ◽

Eric W. Klee ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Intracranial Aneurysms ◽

Point Mutations ◽

Missense Mutations ◽

Loss Of Function ◽

Interaction Domain ◽

Knockout Mouse Model ◽

Whole Exome ◽

Primordial Dwarfism

ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

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