Genetics and genomics of bone marrow failure syndrome

Hyun-Young Kim; Hee-Jin Kim; Sun-Hee Kim

doi:10.5045/br.2022.2022056

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Blood Res 2022; 57(S1):

Published online April 30, 2022

https://doi.org/10.5045/br.2022.2022056

Genetics and genomics of bone marrow failure syndrome

Hyun-Young Kim, Hee-Jin Kim, Sun-Hee Kim

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Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to : Sun-Hee Kim, M.D., Ph.D.
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
E-mail: sunnyhk@skku.edu

Received: March 3, 2022; Revised: April 18, 2022; Accepted: April 19, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Inherited bone marrow failure syndrome (IBMFS) is a group of clinically heterogeneous disorders characterized by significant hematological cytopenias of one or more hematopoietic cell lineages and is associated with an increased risk of cancer. The genetic etiology of IBMFS includes germline mutations impacting several key biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, which may cause four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Although the clinical features of some patients may be typical of a particular IBMFS, overlapping and atypical clinical manifestations and variable penetrance pose diagnostic challenges. Here, we review the clinical and genetic features of the major forms of IBMFS and discuss their molecular genetic diagnosis. Next-generation sequencing-based gene panel testing or whole exome sequencing will help elucidate the genetic causes and underlying mechanisms of this genetically heterogeneous group of diseases.

Keywords Inherited bone marrow failure syndrome, Fanconi anemia, Dyskeratosis congenital, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Somatic genetic rescue

Article

Review Article

Blood Res 2022; 57(S1): S86-S92

Published online April 30, 2022 https://doi.org/10.5045/br.2022.2022056

Genetics and genomics of bone marrow failure syndrome

Hyun-Young Kim, Hee-Jin Kim, Sun-Hee Kim

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to:Sun-Hee Kim, M.D., Ph.D.
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
E-mail: sunnyhk@skku.edu

Received: March 3, 2022; Revised: April 18, 2022; Accepted: April 19, 2022

Abstract

Keywords: Inherited bone marrow failure syndrome, Fanconi anemia, Dyskeratosis congenital, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Somatic genetic rescue

Abstract

Fig 1.

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Figure 1.Schematic of the Fanconi anemia pathway (Hughes and Kurre [7] Br J Haematol 2022;196: 274-87).

Blood Research 2022; 57: S86-S92https://doi.org/10.5045/br.2022.2022056

Fig 2.

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Figure 2.Components of telomere maintenance (Townsley et al. [11] Blood 2014;124:2775-83).

Blood Research 2022; 57: S86-S92https://doi.org/10.5045/br.2022.2022056

Fig 3.

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Figure 3.Mutations of key ribosome components underlying ribosome biogenesis (Ruggero and Shimamura [17] Blood 2014;124:2784-92).

Blood Research 2022; 57: S86-S92https://doi.org/10.5045/br.2022.2022056

Table 1 . Characteristics of major inherited bone marrow failure syndrome..

Categories	Involved genes (estimated proportion^a))	Clinical and laboratory characteristics
Fanconi anemia	AR: FANCA (60%), FANCC (14%), BRCA2 (FANCD1) (3%), FANCD2 (3%), FANCE (3%), FANCF (2%), FANCG (XRCC9) (10%), FANCI (1%), BRIP1 (FANCJ) (2%), FANCL, FANCM, PALB2 (FANCN), RAD51C (FANCO), SLX4 (FANCP), ERCC4 (FANCQ, XPF), BRCA1 (FANCS), UBE2T (FANCT), XRCC2 (FANCU), MAD2L2 (FANCV, REV7), RFWD3 (FANCW). AD: RAD51 (FANCR). XLR: FANCB (2%).	Short stature, upper limb (radial ray) abnormalities, skin pigmentation (caféau lait macules), renal malformations, microcephaly. May have features of VACTERL-H. Pancytopenia, macrocytosis, elevated HbF, increased chromosome breakage.
Dyskeratosis congenital (DC) and related telomere biology disorders	XLR: DKC1 (15–20%). AD: TINF2 (TIN2) (11–20%), TERC (5%), NAF1. AR: CTC1, NOP10, NHP2, WRAP53 (TCAB1), STN1, POT1. AD and AR: RTEL1 (5–10%), TERT (5%), ACD (TPP1), PARN.	Classic triad of DC: nail dystrophy, oral leukoplakia, skin pigmentation. Pulmonary fibrosis, liver disease. Pancytopenia, macrocytosis, very short telomeres.
Diamond-Blackfan anemia	AD: RPS19 (25%), RPL11 (6–7%), RPS26 (6%), RPS10 (2–3%), RPL35A (3%), RPS24 (2%), RPS17 (1%), RPL5, RPL15, RPL17, RPL19, RPL26, RPL31, RPS7, RPS19, RPS20, RPS28, RPS29. XLR: GATA1, TSR2.	Cleft lip or palate, thumb abnormalities, cardiac malformations, short stature. Anemia, macrocytosis, reticulocytopenia.
Shwachman-Diamond syndrome	AR: SBDS (95%), DNAJC21, EFL1. AD: SRP54.	Exocrine pancreatic insufficiency, skeletal abnormalities. Neutropenia, low serum isoamylase, low serum trypsinogen.

^a)Estimated proportion of patients are not described for genes that are rarely involved..

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; VACTERL-H, vertebral anomalies, anal atresia, cardiac anomalies, tracheo-esophageal fistula, esophageal atresia, renal structural anomalies, upper limb anomalies, hydrocephalus; XLR, X-linked recessive..