Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing
Abstract: Diamond-Blackfan anemia syndrome (DBAS) is a rare congenital disorder with variable penetrance and expressivity and is characterized by pure red cell aplasia that typically manifests as early-onset chronic macrocytic or normocytic anemia and is often associated with other congenital anomal...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
|
| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925001405 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850272585269379072 |
|---|---|
| author | Ting Wen Steven E. Boyden Caleb M. Hocutt Robert G. Lewis Erin E. Baldwin Jennie Vagher Ashley Andrews Thomas J. Nicholas Alexander Chapin Elaine M. Fan Lorenzo D. Botto Pinar Bayrak-Toydemir Rong Mao Jessica A. Meznarich |
| author_facet | Ting Wen Steven E. Boyden Caleb M. Hocutt Robert G. Lewis Erin E. Baldwin Jennie Vagher Ashley Andrews Thomas J. Nicholas Alexander Chapin Elaine M. Fan Lorenzo D. Botto Pinar Bayrak-Toydemir Rong Mao Jessica A. Meznarich |
| author_sort | Ting Wen |
| collection | DOAJ |
| description | Abstract: Diamond-Blackfan anemia syndrome (DBAS) is a rare congenital disorder with variable penetrance and expressivity and is characterized by pure red cell aplasia that typically manifests as early-onset chronic macrocytic or normocytic anemia and is often associated with other congenital anomalies. DBAS is etiologically heterogeneous with >20 known DBAS-associated genes that encode small and large ribosomal protein subunits and an inheritance pattern that is largely autosomal dominant or sporadic. We report 2 DBAS cases with previous negative genetic testing, which included targeted gene panels, karyotype analysis, chromosome breakage analysis, and whole exome sequencing. Although clinical whole genome sequencing (WGS) was initially negative, in-depth reanalysis identified 2 novel noncoding variants in the RPS gene family, namely a maternally inherited splicing variant at the end of the first noncoding exon in RPS7 (NM_001011.4, c.-19G>C) in family 1 and a deep intronic de novo variant in RPS19 (NM_001022.4, c.172+350C>T) in family 2. In family 1, several maternal relatives were identified who shared the same variant through cascade testing; clinically, they exhibited variable degrees of anemia and elevated erythrocyte adenosine deaminase activity, a marker for DBAS. RNA sequencing analysis demonstrated deleterious functional consequences for both noncoding variants. In case 1, hematopoietic stem cell transplant with an unaffected matched sibling donor who did not carry the variant successfully cured the congenital anemia. This study identified novel noncoding variants and underscores the clinical utility of WGS in accelerating diagnosis and improving care for rare genetic disorders, particularly when timely treatment decisions are critically important. |
| format | Article |
| id | doaj-art-9d6c520365564cbc8e40fc75fd93aa91 |
| institution | OA Journals |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-9d6c520365564cbc8e40fc75fd93aa912025-08-20T01:51:45ZengElsevierBlood Advances2473-95292025-05-019102443245210.1182/bloodadvances.2024015347Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencingTing Wen0Steven E. Boyden1Caleb M. Hocutt2Robert G. Lewis3Erin E. Baldwin4Jennie Vagher5Ashley Andrews6Thomas J. Nicholas7Alexander Chapin8Elaine M. Fan9Lorenzo D. Botto10Pinar Bayrak-Toydemir11Rong Mao12Jessica A. Meznarich13ARUP Laboratories, Salt Lake City, UT; Department of Pathology, University of Utah, Salt Lake City, UT; Department of Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, MI; Correspondence: Ting Wen, Department of Pathology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202;Department of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, UTDivision of Pediatric Hematology and Oncology, Department of Pediatrics, University of Utah, Salt Lake City, UT; Primary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UTARUP Laboratories, Salt Lake City, UT; Department of Pathology, University of Utah, Salt Lake City, UTPrimary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UT; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UTHuntsman Cancer Institute, University of Utah, Salt Lake City, UTPrimary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UT; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UTDepartment of Human Genetics, Utah Center for Genetic Discovery, Salt Lake City, UTARUP Laboratories, Salt Lake City, UTDivision of Pediatric Hematology and Oncology, Department of Pediatrics, University of Utah, Salt Lake City, UT; Primary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UTDivision of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UTARUP Laboratories, Salt Lake City, UT; Department of Pathology, University of Utah, Salt Lake City, UTARUP Laboratories, Salt Lake City, UT; Department of Pathology, University of Utah, Salt Lake City, UTDivision of Pediatric Hematology and Oncology, Department of Pediatrics, University of Utah, Salt Lake City, UT; Primary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UT; Jessica A. Meznarich, Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108;Abstract: Diamond-Blackfan anemia syndrome (DBAS) is a rare congenital disorder with variable penetrance and expressivity and is characterized by pure red cell aplasia that typically manifests as early-onset chronic macrocytic or normocytic anemia and is often associated with other congenital anomalies. DBAS is etiologically heterogeneous with >20 known DBAS-associated genes that encode small and large ribosomal protein subunits and an inheritance pattern that is largely autosomal dominant or sporadic. We report 2 DBAS cases with previous negative genetic testing, which included targeted gene panels, karyotype analysis, chromosome breakage analysis, and whole exome sequencing. Although clinical whole genome sequencing (WGS) was initially negative, in-depth reanalysis identified 2 novel noncoding variants in the RPS gene family, namely a maternally inherited splicing variant at the end of the first noncoding exon in RPS7 (NM_001011.4, c.-19G>C) in family 1 and a deep intronic de novo variant in RPS19 (NM_001022.4, c.172+350C>T) in family 2. In family 1, several maternal relatives were identified who shared the same variant through cascade testing; clinically, they exhibited variable degrees of anemia and elevated erythrocyte adenosine deaminase activity, a marker for DBAS. RNA sequencing analysis demonstrated deleterious functional consequences for both noncoding variants. In case 1, hematopoietic stem cell transplant with an unaffected matched sibling donor who did not carry the variant successfully cured the congenital anemia. This study identified novel noncoding variants and underscores the clinical utility of WGS in accelerating diagnosis and improving care for rare genetic disorders, particularly when timely treatment decisions are critically important.http://www.sciencedirect.com/science/article/pii/S2473952925001405 |
| spellingShingle | Ting Wen Steven E. Boyden Caleb M. Hocutt Robert G. Lewis Erin E. Baldwin Jennie Vagher Ashley Andrews Thomas J. Nicholas Alexander Chapin Elaine M. Fan Lorenzo D. Botto Pinar Bayrak-Toydemir Rong Mao Jessica A. Meznarich Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing Blood Advances |
| title | Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing |
| title_full | Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing |
| title_fullStr | Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing |
| title_full_unstemmed | Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing |
| title_short | Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing |
| title_sort | identification of 2 novel noncoding variants in patients with diamond blackfan anemia syndrome by whole genome sequencing |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925001405 |
| work_keys_str_mv | AT tingwen identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT steveneboyden identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT calebmhocutt identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT robertglewis identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT erinebaldwin identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT jennievagher identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT ashleyandrews identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT thomasjnicholas identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT alexanderchapin identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT elainemfan identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT lorenzodbotto identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT pinarbayraktoydemir identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT rongmao identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing AT jessicaameznarich identificationof2novelnoncodingvariantsinpatientswithdiamondblackfananemiasyndromebywholegenomesequencing |