Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes

被引：18

作者：

Blombery, Piers ^{[1
,2
,3
]}

Fox, Lucy C. ^{[3
,4
,5
]}

Ryland, Georgina L. ^{[3
]}

Thompson, Ella R. ^{[2
,3
]}

Lickiss, Jennifer ^{[3
]}

McBean, Michelle ^{[3
]}

Yerneni, Satwica ^{[3
]}

Hughes, David ^{[6
]}

Greenway, Anthea ^{[6
]}

Mechinaud, Francoise ^{[6
]}

Wood, Erica M. ^{[5
]}

Lieschke, Graham J. ^{[1
,7
]}

Szer, Jeff ^{[1
]}

Barbaro, Pasquale ^{[8
,9
]}

Roy, John ^{[8
,9
]}

Wight, Joel ^{[10
]}

Lynch, Elly ^{[11
,12
,13
]}

Martyn, Melissa ^{[11
,12
,13
]}

Gaff, Clara ^{[2
,11
,13
]}

Ritchie, David ^{[1
]}

机构：

[1] Royal Melbourne Hosp, Peter MacCallum Canc Ctr, Clin Hematol, Melbourne, Vic, Australia

[2] Univ Melbourne, Melbourne, Vic, Australia

[3] Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic, Australia

[4] Epworth Healthcare, Melbourne, Vic, Australia

[5] Monash Univ, Sch Publ Hlth & Prevent Med, Transfus Res Unit, Melbourne, Vic, Australia

[6] Royal Childrens Hosp, Melbourne, Vic, Australia

[7] Monash Univ, Australian Regenerat Med Inst, Melbourne, Vic, Australia

[8] Childrens Hlth Queensland, South Brisbane, Qld, Australia

[9] Univ Queensland, South Brisbane, Qld, Australia

[10] Austin Hlth, Dept Hematol, Melbourne, Vic, Australia

[11] Melbourne Genom Hlth Alliance, Melbourne, Vic, Australia

[12] Victorian Clin Genet Serv, Melbourne, Vic, Australia

[13] Murdoch Childrens Res Inst, Melbourne, Vic, Australia

来源：

HAEMATOLOGICA | 2021年 / 106卷 / 01期

关键词：

SEVERE CONGENITAL NEUTROPENIA; RIBOSOMAL-PROTEIN S19; FANCONI-ANEMIA; SOMATIC MUTATIONS; HAX1; MUTATIONS; BREAST-CANCER; GENE; DNA; HEMATOPOIESIS; GUIDELINES;

D O I：

10.3324/haematol.2019.237693

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndromes (median age 24 years, range: 3 months 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12 of 23), 53% (25 of 47) and 56% (25 of 45) respectively. Genomic characterization resulted in a change of diagnosis in 30 of 115 (26%) including the identification of germline causes for 3 of 47 and 16 of 45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.

引用

页码：64 / 73

页数：10

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