Disease mechanisms of ZMYM2 mutations, a new monogenic cause for congenital anomalies of the kidney and urinary tract
Human Genetics
Final Report Abstract
Congenital anomalies of the kidneys and urinary tract (CAKUT) represent a heterogenous group of diseases that are caused by an impaired embryonic development of the genitourinary tract. CAKUT is the most common birth defect and the most common cause of chronic kidney disease in children and young adults. In the past years, >170 monogenic causes of isolated or syndromic CAKUT (i.e., the presence of CAKUT and extrarenal manifestations) have been identified, primarily by utilizing whole exome sequencing (WES). However, the majority of cases (~85%) still remains without an identified monogenic cause, and it is likely that additional, yet unknown genetic causes of CAKUT exist. The project was initially planned (1) to investigate additional families with CAKUT by WES in order to further understand the genetic landscape and to identify novel candidate genes, and (2) to functionally characterize missense mutations in the gene ZMYM2, which had earlier been identified as a novel candidate gene for CAKUT in the host lab. The latter subproject was not further followed up due to newly emerged evidence that missense mutations in ZMYM2, in contrast to truncating mutations, appeared unlikely to be pathogenic in CAKUT. Thus, the work was focused on WES-based analyses of probands with CAKUT and other congenital malformations. In total, in a joint work, DNA from ~1,000 probands was processed and subjected to WES, followed by an analysis of variants in the 174 genes known to cause CAKUT, if mutated. In addition, reverse phenotyping, in which the patient’s physician is asked to reexamine the patient on specific signs/symptoms of the assumed disease based on the genotype identified by WES, was systematically applied in equivocal cases. WES in conjunction with reverse phenotyping enabled the establishment of a strong genotype-phenotype correlation and thus reveal a monogenic cause of CAKUT in 83 of 731 (11.4%) families with CAKUT from this international cohort. It could be shown that reverse phenotyping greatly increases the diagnostic yield of WES by detecting previously unknown syndromic features in 19 of 83 (22.9%) families. Furthermore, in a subset of families in whom no causative variant in a known gene was found, a further analysis under a candidate gene hypothesis was conducted, which, for example, led to the identification of several Forkhead Box (FOX) transcription factors as potential novel candidate genes for CAKUT. Spina bifida, another common congenital malformation, shares many pathomechanisms and phenotypic features with CAKUT. However, despite several hints that render a monogenic causation likely, the evidence on monogenic causes of spina bifida is rare. In a pilot study, we enrolled 50 families with SB and subjected them to WES. Using a dual approach, by generating a list of potential candidate genes derived from mouse models as well as utilizing an unbiased exome-wide search for deleterious variants, we identified 18 potential novel candidate genes for spina bifida. For both disease entities, further functional analyses are needed to delineate the pathomechanisms of the identifies candidate genes.
Publications
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DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation. Am J Hum Genet 2020; 107 (6): 1113-28
Schneider R, Deutsch K, Hoeprich GJ, Marquez J, Hermle T, Braun DA, Seltzsam S, Kitzler TM, Mao Y, Buerger F, Majmundar AJ, Onuchic-Whitford AC, Kolvenbach CM, Schierbaum L, Schneider S, Halawi AA, Nakayama M, Mann N, Connaughton DM, Klämbt V, Wagner M, Riedhammer KM, Renders L, Katsura Y, Thumkeo D, Soliman NA, Mane S, Lifton RP, Shril S, Khokha MK, Hoefele J, Goode BL, Hildebrandt F
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A truncating NRIP1 variant in an Arabic family with congenital anomalies of the kidneys and urinary tract. Am J Med Genet A 2021
Zheng B, Wang C Seltzsam S, Schneider S, Schierbaum L, Wu CW, Dai R, Connaughton DM, Nakayama M, Mann N, Bauer SB, Awad HS, Eid LA, Tasic V, Shril S, Hildebrandt F
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Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT. Genet Med 2021
Seltzsam S, Wang C, Zheng B, Mann N, Connaughton DM, Wu CW, Schneider S, Schierbaum L, Kause F, Kolvenbach CM, Nakayama M, Dai R, Ottlewski I, Schneider R, Deutsch K, Buerger F, Klämbt V, Mao Y, Onuchic-Whitford AC, Nicolas-Frank C, Yousef K, Pantel D, Lai EW, Salmanullah D, Majmundar AJ, Bauer SB, Rodig NM, Somers MJG, Traum AZ, Stein DR, Daga A, Baum MA, Daouk GH, Tasic V, Awad HS, Eid LA, El Desoky S, Shalaby M, Kari JA, Fathy HM, Soliman NA, Mane SM, Shril S, Ferguson MA, Hildebrandt F
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Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract. Nephrol Dial Transplant 2021
Zheng B, Seltzsam S, Wang C, Schierbaum L, Schneider S, Wu CW, Dai R, Connaughton DM, Nakayama M, Mann N, Stajic N, Mane S, Bauer SB, Tasic V, Nam HJ, Shril S, Hildebrandt F
