Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT
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Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT. / Seltzsam, Steve; Wang, Chunyan; Zheng, Bixia; Mann, Nina; Connaughton, Dervla M; Wu, Chen-Han Wilfred; Schneider, Sophia; Schierbaum, Luca; Kause, Franziska; Kolvenbach, Caroline M; Nakayama, Makiko; Dai, Rufeng; Ottlewski, Isabel; Schneider, Ronen; Deutsch, Konstantin; Buerger, Florian; Klämbt, Verena; Mao, Youying; Onuchic-Whitford, Ana C; Nicolas-Frank, Camille; Yousef, Kirollos; Pantel, Dalia; Lai, Ethan W; Salmanullah, Daanya; Majmundar, Amar J; Bauer, Stuart B; Rodig, Nancy M; Somers, Michael J G; Traum, Avram Z; Stein, Deborah R; Daga, Ankana; Baum, Michelle A; Daouk, Ghaleb H; Tasic, Velibor; Awad, Hazem S; Eid, Loai A; El Desoky, Sherif; Shalaby, Mohammed; Kari, Jameela A; Fathy, Hanan M; Soliman, Neveen A; Mane, Shrikant M; Shril, Shirlee; Ferguson, Michael A; Hildebrandt, Friedhelm.
In: GENET MED, Vol. 24, No. 2, 02.2022, p. 307-318.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT
AU - Seltzsam, Steve
AU - Wang, Chunyan
AU - Zheng, Bixia
AU - Mann, Nina
AU - Connaughton, Dervla M
AU - Wu, Chen-Han Wilfred
AU - Schneider, Sophia
AU - Schierbaum, Luca
AU - Kause, Franziska
AU - Kolvenbach, Caroline M
AU - Nakayama, Makiko
AU - Dai, Rufeng
AU - Ottlewski, Isabel
AU - Schneider, Ronen
AU - Deutsch, Konstantin
AU - Buerger, Florian
AU - Klämbt, Verena
AU - Mao, Youying
AU - Onuchic-Whitford, Ana C
AU - Nicolas-Frank, Camille
AU - Yousef, Kirollos
AU - Pantel, Dalia
AU - Lai, Ethan W
AU - Salmanullah, Daanya
AU - Majmundar, Amar J
AU - Bauer, Stuart B
AU - Rodig, Nancy M
AU - Somers, Michael J G
AU - Traum, Avram Z
AU - Stein, Deborah R
AU - Daga, Ankana
AU - Baum, Michelle A
AU - Daouk, Ghaleb H
AU - Tasic, Velibor
AU - Awad, Hazem S
AU - Eid, Loai A
AU - El Desoky, Sherif
AU - Shalaby, Mohammed
AU - Kari, Jameela A
AU - Fathy, Hanan M
AU - Soliman, Neveen A
AU - Mane, Shrikant M
AU - Shril, Shirlee
AU - Ferguson, Michael A
AU - Hildebrandt, Friedhelm
N1 - Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
PY - 2022/2
Y1 - 2022/2
N2 - PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES.METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping.RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation.CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.
AB - PURPOSE: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES.METHODS: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping.RESULTS: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation.CONCLUSION: We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.
KW - Alleles
KW - Exome/genetics
KW - Humans
KW - Kidney/abnormalities
KW - Urinary Tract
KW - Urogenital Abnormalities/genetics
KW - Vesico-Ureteral Reflux
U2 - 10.1016/j.gim.2021.09.010
DO - 10.1016/j.gim.2021.09.010
M3 - SCORING: Journal article
C2 - 34906515
VL - 24
SP - 307
EP - 318
JO - GENET MED
JF - GENET MED
SN - 1098-3600
IS - 2
ER -