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2 results on '"Danielle C. Kimble"'

1. A novel de novo TP63 mutation in whole‐exome sequencing of a Syrian family with Oral cleft and ectrodactyly

Author

Claire L. Simpson, Danielle C. Kimble, Settara C. Chandrasekharappa, NISC Comparative Sequencing Program, Khalid Alqosayer, Emily Holzinger, Blake Carrington, John McElderry, Raman Sood, Ghiath Al‐Souqi, Hasan Albacha‐Hejazi, and Joan E. Bailey‐Wilson

Subjects
cleft lip, cleft palate, limb deformities, congenital, whole‐exome sequencing, Genetics, QH426-470
Abstract

Abstract Background Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole‐exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly but not ectodermal dysplasia as typically seen in ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome‐3. A paternal uncle with only an oral cleft was deceased and unavailable for analysis. Methods Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing, and pathogenicity assessed by knocking out the tp63 gene in zebrafish to evaluate its role during zebrafish development. Results Twenty‐eight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G > T, p.Arg319Leu), and confirmed by Sanger sequencing. Conclusion TP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. Two known mutations in the same codon (c.956G > A, p.(Arg319His; rs121908839, c.955C > T), p.Arg319Cys) cause ectrodactyly, providing evidence that mutating this codon is deleterious. While this TP63 mutation is the best candidate for the patient's clinical presentation, whether it is responsible for the entire phenotype is unclear. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days post‐fertilization (dpf). The embryonic phenotype could not be rescued by injection of zebrafish or human messenger RNA (mRNA). Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.

Published
2023
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2. Somatic mosaicism of an intragenicFANCBduplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype

Author

Adrianna Vlachos, Rajalakshmi S. Asur, James W. Thomas, Morgan Park, Frank X. Donovan, Moonjung Jung, Agata Smogorzewska, Arleen D. Auerbach, Danielle C. Kimble, Settara C. Chandrasekharappa, Raymond J. Noonan, Francis P. Lach, Peter S. Chines, and Aparna Kamat

Subjects
Male, 0301 basic medicine, milder phenotype, Adolescent, Genotype, intragenic duplication, Biology, FANCB, Homology (biology), droplet digital PCR, 03 medical and health sciences, Exon, Genes, X-Linked, Fanconi anemia, Gene Duplication, FANCD2, Gene duplication, Genetics, medicine, Humans, Allele, Molecular Biology, Alleles, Genetics (clinical), revertant mosaicism, Blood Cells, Base Sequence, Mosaicism, Breakpoint, Exons, Original Articles, Fibroblasts, medicine.disease, Fanconi Anemia Complementation Group Proteins, 3. Good health, Fanconi Anemia, Phenotype, 030104 developmental biology, Original Article
Abstract

Background Fanconi anemia (FA) is a rare disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer. Patients harboring X‐linked FANCB pathogenic variants usually present with severe congenital malformations resembling VACTERL syndrome with hydrocephalus. Methods We employed the diepoxybutane (DEB) test for FA diagnosis, arrayCGH for detection of duplication, targeted capture and next‐gen sequencing for defining the duplication breakpoint, PacBio sequencing of full‐length FANCB aberrant transcript, FANCD2 ubiquitination and foci formation assays for the evaluation of FANCB protein function by viral transduction of FANCB‐null cells with lentiviral FANCB WT and mutant expression constructs, and droplet digital PCR for quantitation of the duplication in the genomic DNA and cDNA. Results We describe here an FA‐B patient with a mild phenotype. The DEB diagnostic test for FA revealed somatic mosaicism. We identified a 9154 bp intragenic duplication in FANCB, covering the first coding exon 3 and the flanking regions. A four bp homology (GTAG) present at both ends of the breakpoint is consistent with microhomology‐mediated duplication mechanism. The duplicated allele gives rise to an aberrant transcript containing exon 3 duplication, predicted to introduce a stop codon in FANCB protein (p.A319*). Duplication levels in the peripheral blood DNA declined from 93% to 7.9% in the span of eleven years. Moreover, the patient fibroblasts have shown 8% of wild‐type (WT) allele and his carrier mother showed higher than expected levels of WT allele (79% vs. 50%) in peripheral blood, suggesting that the duplication was highly unstable. Conclusion Unlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA‐B patient described here.

Published
2017
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