ESPN 51th Annual Meeting

ESPN 2018


 
Next-generation sequencing as a useful diagnostic tool in patients with kidney disorders and skeletal abnormalities
MICHAELA STIPPEL 1 KORBINIAN M. RIEDHAMMER 1 Matthias C. Braunisch 2 Pierre Maurice Herr 1 Michaela Geßner 3 Roman Günthner 2 Robin Satanovskij 2 Martin Bald 4 Christoph Schmaderer 2 Lutz Renders 2 Julia Hoefele 1

1- INSTITUTE OF HUMAN GENETICS, KLINIKUM RECHTS DER ISAR, TECHNICAL UNIVERSITY OF MUNICH, MUNICH, GERMANY
2- DEPARTMENT OF NEPHROLOGY, KLINIKUM RECHTS DER ISAR, TECHNICAL UNIVERSITY OF MUNICH, MUNICH, GERMANY
3- UNIVERSITY CHILDREN’S HOSPITAL, PEDIATRIC NEPHROLOGY, TÜBINGEN, GERMANY
4- OLGAHOSPITAL, STUTTGART, GERMANY
 
Introduction:

Hereditary kidney disorders are both clinically and genetically heterogeneous and pose a diagnostic challenge. Exome sequencing (ES) has become a powerful tool to unravel complex genetic disorders. We are presenting five independent families with six individuals affected by a kidney disorder associated with skeletal abnormalities.

Material and methods:

ES of the index patient and – if available – of the parents was performed.

Results:

The overall diagnostic yield in 183 families with a presumed hereditary kidney disease was 54%. Concerning patients with a kidney disorder associated with a skeletal phenotype, a yield of 100 % was reached. In a 3-year-old patient with proteinuria and skeletal dysplasia, we could identify a heterozygous de novo missense variant in MAFB (multicentric carpotarsal osteolysis syndrome). In an 8-year-old girl with kidney hypoplasia and short stature, we found a heterozygous 2.9 kb deletion comprising the complete SIX2 gene. Haploinsufficiency of SIX2 has not been connected to a renal phenotype yet. We detected a complex allele (one near-splice, one nonsense variant; both in a homozygous state) in BBS1 in two brothers (2 and 15 years old) with a complex nephroskeletal phenotype. In a 14-year-old boy with kidney dysplasia and hypoplastic clavicles we could identify a de novo frameshift variant in PBX1. PBX1 was not a known disease gene and there was only one report linking it to a monogenic kidney disease at that time. Furthermore, we found a nonsense variant in PBX1 in a 38-year-old patient with kidney hypoplasia/dysplasia and short stature.

Conclusions:

Our data supports that ES is an effective diagnostic tool in syndromic hereditary kidney disorders. Furthermore, it is also an efficient tool, as only 1 % of the genome is exomic but approximately 85 % of disease-causing variants are believed to be located in the coding regions of the genome.