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. 2024 Oct 1;109(10):3383-3390.
doi: 10.3324/haematol.2024.285055.

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings

Ozge Ceyhan-Birsoy  1 , Elise Fiala  2 , Satshil Rana  1 , Margaret Sheehan  3 , Jennifer Kennedy  3 , Zarina Yelskaya  1 , Vikas Rai  1 , Yirong Li  1 , Ciyu Yang  1 , Donna Wong  1 , Ivelise Rijo  1 , Jacklyn Casanova  1 , Joshua Somar  1 , Nikita Mehta  1 , Hyeonjin Park  1 , Silvana Ostafi  1 , Kanika Arora  1 , Angelika Padunan  3 , Mark D Ewalt  1 , Umut Aypar  1 , Panieh Terraf  1 , Maksym Misyura  1 , Sofia Haque  4 , Gerald G Behr  4 , Tamanna Haque  3 , Maria Sulis  2 , Mark B Geyer  3 , Christopher Forlenza  2 , Meghan C Thompson  3 , Maria Carlo  3 , Alicia Latham  3 , Ying Liu  3 , Ahmet Zehir  1 , Rose Brannon  1 , Michael Berger  1 , Luis A Diaz Jr  3 , Ahmet Dogan  1 , Marc Ladanyi  1 , Kseniya Petrova-Drus  1 , Khedoudja Nafa  1 , Kenneth Offit  3 , Maria Arcila  1 , Zsofia K Stadler  5 , Michael F Walsh  6 , Diana Mandelker  7
Affiliations

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings

Ozge Ceyhan-Birsoy et al. Haematologica. .
No abstract available

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Figures

Figure 1.
Figure 1.
Validation of the Germline MSK-IMPACT-Heme panel and overview of the MSK-IMPACT-Heme workflow. (A) Each target exon and adjacent splice sites (±20 bp) of 68 genes that were common between MSK-IMPACT-Heme and MSK-IMPACT had sufficient (>20X) and equivalent coverage in tested blood, saliva, and nail specimens. (B) Representative copy number plots demonstrating the detection of a single exon (MSH2 exon 1) deletion and an intragenic multi-exon (MSH3 exon 3-23) deletion in validation of copy number variant calling using DNA isolated from nail specimens by Germline MSK-IMPACT-Heme. (C) Representative detection of a small deletion (CHEK2 c.1100delC) variant by the Germline MSK-IMPACT-Heme next-generation sequencing panel and Sanger sequencing using DNA isolated from nail specimens. (D) Overview of the MSK-IMPACT-Heme workflow. Patients referred by their clinical providers are consented for paired tumor-normal sequencing and germline analysis. A sample for a source of normal DNA (nail or saliva) and a sample for a source of tumor DNA (blood, bone marrow, lymph node, or other tissue) are collected. DNA is extracted from the samples, sequence libraries are prepared and captured using MSK-IMPACT-Heme probes. Sequencing is performed and data are analyzed through a custom bioinformatics pipeline to detect and annotate variants. Results are interpreted, classified, and reported by clinical molecular geneticists and molecular pathologists. Reports are transferred to the patient's electronic medical records. Figure 1D was created partly with BioRender.com. T/N: target to normal; NGS: next-generation sequencing.
Figure 2.
Figure 2.
Patients with germline pathogenic/likely pathogenic variants in genes associated with a predisposition to hematologic malignancies. (A) Patient with biallelic germline pathogenic/likely pathogenic variants (gPV) in FANCA diagnosed with Fanconi anemia. Left. Pedigree of the patient with biallelic FANCA gPV. Middle. A representative core biopsy involved by myelodysplasia-related acute myeloid leukemia (hematoxylin & eosin [H&E], 10X original magnification) with hypercellularity, decreased maturing trilineage hematopoiesis, and increased numbers of blasts in clusters (H&E, 40X original magnification) accounting for 50% of cellularity (highlighted by CD34 immunohistology, 10X original magnification). A right-sided aortic arch was identified in the patient. (B) Patient with biallelic gPV in AT M diagnosed with ataxia telangiectasia. Left. Pedigree of the patient with biallelic ATM gPV. Right. A bone marrow biopsy revealed hypercellular marrow (H&E, 4X original magnification) extensively involved by an atypical lymphoid infiltrate (H&E, 4X original magnification) with large-size neoplastic mature B cells (H&E, 40X original magnification and CD20 immunohistology 20X original magnification) and a background of numerous reactive T cells (CD3 immunohistology 20X original magnification), overall consistent with diffuse large B-cell lymphoma. (C) Patient with biallelic gPV in MSH6 diagnosed with congenital mismatch repair deficiency. Left. Pedigree of the patient with biallelic MSH6 gPV. Middle. Colonoscopy 4 months after the initial presentation revealed several colonic polyps, including hyperplas tic, tubular adenomas, and a tubulovillous adenoma (H&E, 2X original magnification) with villous architecture and columnar cells showing focal high-grade dysplasia (H&E, 20X original magnification). Right. Brain magnetic resonance imaging of the patient showing nonspecific hyperintensities. (D) Pedigree of the patient with ETV6 gPV. The ETV6 gPV was identified in the patient with a history of chronic myelomonocytic leukemia and thrombocytopenia and segregated in her daughter with a history of thrombocytopenia. (E) Pedigree of the patient with RUNX1 gPV. (F) Left. Pedigree of the patient with a DDX41 c.916C>T (p.Gln306*) gPV. Right. Using next-generation sequencing a germline DDX41 c.916C>T (p.Gln306*) variant was detected in the patient’s nail and bone marrow DNA and a somatic DDX41 c.1574G>A (p.Arg574His) variant was detected in her bone marrow DNA sample at a variant allele fraction of 13% (right panel). ca: cancer; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; DLBCL: diffuse large B-cell lymphoma; ALL: acute lymphoblastic leukemia; yrs: years; CMML: chronic myelomonocytic leukemia; VAF: variant allele fraction.
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