ESPN 50th Annual Meeting

ESPN 2017


 
Genomic imbalances in children with chronic kidney disease
LIPSKA-ZIęTKIEWICZ BEATA S. 1 KOCZKOWSKA MAGDALENA 1 WONG CRAIG 3 BAYAZIT AYSUN K. 4 DUZOVA ALI 5 CANPOLAT NUR 6 KAPLAN BULUT IPEK 7 AZUKAITIS KAROLIS 8 NIEMIRSKA ANNA 1 RANCHIN BRUNO 9 SHROFF RUKSHANA 10 SEVER LALE 6 PARIPOVIC DUSAN 11 CANDAN CENGIZ 12 WUHL ELKE 2 YILDIZ NURDAN 13 YALCINKAYA FATOS 14 MELK ANETTE 15 QUERFELD UWE 16 SCHAEFER FRANZ 2

1- DEPARTMENT OF BIOLOGY AND MEDICAL GENETICS, MEDICAL UNIVERSITY OF GDAńSK, POLAND
2- 2. DIVISION OF PEDIATRIC NEPHROLOGY, CENTER FOR PEDIATRICS AND ADOLESCENT MEDICINE, UNIVERSITY OF HEIDELBERG, HEIDELBERG, GERMANY
3- 3. DEPARTMENT OF PEDIATRICS, DIVISION OF NEPHROLOGY, UNIVERSITY OF NEW MEXICO CHILDRENS HOSPITAL, ALBUQUERQUE, USA
4- 4. DEPARTMENT OF PEDIATRIC NEPHROLOGY, CUKUROVA UNIVERSITY, ADANA, TURKEY
5- DEPARTMENT OF PEDIATRIC NEPHROLOGY, HACETTEPE UNIVERSITY FACULTY OF MEDICINE, ANKARA, TURKEY
6- DEPARTMENT OF PEDIATRICS, DIVISION OF PEDIATRIC NEPHROLOGY, İSTANBUL UNIVERSITY CERRAHPAŞA
7- DEPARTMENT OF PEDIATRIC NEPHROLOGY, EGE UNIVERSITY MEDICAL FACULTY, IZMIR, TURKEY
8- VILNIUS UNIVERSITY CHILDREN`S HOSPITAL, VILNIUS, LITHUANIA
9- SERVICE DE PéDIATRIE AND INSERM U820, CENTRE DE RéFéRENCE DES MALADIES RéNALES RARES, HôPITAL FEMME MèRE ENFANT & UNIVERSITé DE LYON, FRANCE
10- RENAL UNIT, GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS FOUNDATION TRUST, LONDON, UNITED KINGDOM
11- NEPHROLOGY DEPARTMENT, UNIVERSITY CHILDRENS HOSPITAL, BELGRADE, SERBIA
12- DIVISION OF PEDIATRIC NEPHROLOGY, ISTANBUL MEDENIYET UNIVERSITY, ISTANBUL, TURKEY
13- DEPARTMENT OF PEDIATRIC NEPHROLOGY, MARMARA UNIVERSITY MEDICAL FACULTY, ISTANBUL, TURKEY
14- ANKARA UNIVERSITY SCHOOL OF MEDICINE, DEPARTMENT OF PEDIATRIC NEPHROLOGY, ANKARA, TURKEY
15- PEDIATRIC KIDNEY, LIVER AND METABOLIC DISEASE, MHH CHILDREN´S HOSPITAL, HANNOVER, GERMANY
16- PEDIATRIC NEPHROLOGY CHARITé, UNIVERSITY CHILDRENS HOSPITAL BERLIN, BERLIN, GERMANY
 
Introduction:

Chromosomal microarrays are routinely utilized for genetic testing of developmental delay/intellectual disability, autism spectrum disorders  or multiple congenital anomalies. Here, we studied the prevalence of DNA copy number variations (CNVs) in a large cohort of European and Turkish children presenting with chronic kidney disease. 

Material and methods:

986 consecutive patients enrolled in the ESCAPE and 4C studies were genotyped using 2.4 million SNP Illumina microarray. Data was interpreted in accordance to ACMG Practice Guidelines using the Nexus Copy Number software. Filtering criteria included the size of imbalance, overlap with known benign CNVs, gene content, and verification against Decipher and ISCA databases. 

Results:

890 (90.3%) samples were eventually eligible to detailed genotype-phenotype correlations, of these 74 (8.3%) were classified as having a definite pathogenic genomic aberration and another 11 as having a likely pathogenic CNV. In addition, 34 patients were found to have a heterozygous variant in a known AR gene associated with a hereditary kidney disorder. Definite diagnoses were made in 4.7% of individuals with CAKUT, 2.8% of patients with a glomerulopathy and 27.9% of those with a tubulointerstitial disorder.  

The most frequent imbalances were chromosome 2q13 homozygous deletions of the NPHP1 region (n=37), 1q21.1 deletions including the CHD1L gene (n=7), rearrangements at 22q11.2 (n=7) and 17q12 deletions encompassing the HNF1B locus (n=6). Small, including single gene, rearrangements were reported for 56 genes including CTNS, PKD1, TSC2, ROBO2, NOTCH2  and TFAP2A loci

Conclusions:

Clinical diagnosis was revised in 10 CAKUT cases (HNF1ß nephropathy (n=5); nephronophthisis (n=5)) and in one case of clinically suspected Bardet-Biedl syndrome (nephronophthisis).  The detection of a genomic imbalance allowed for reverse phenotyping in most cases, resulting in clinical interventions such as evaluation for extra-renal involvement and implementation of multidisciplinary care. 

Genomic imbalances account for a significant portion of children with CKD and their diagnosis has important implications for genetic counseling and clinical management.