Identification of a Gene for Renal-Hepatic-Pancreatic Dysplasia by Microarray-Based Homozygosity Mapping

• Published in: The Journal of molecular diagnostics : JMD Vol. 12; no. 1; pp. 125 - 131
• Main Authors: Fiskerstrand, Torunn, Houge, Gunnar, Sund, Staale, Scheie, David, Leh, Sabine, Boman, Helge, Knappskog, Per M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2010; ASIP; American Society for Investigative Pathology
• Subjects: Abnormalities, Multiple - genetics; Abortion, Eugenic; Calmodulin-Binding Proteins - genetics; Chromosome Mapping; Chromosomes, Human, Pair 3 - genetics; Consultations in Molecular Diagnostics; Female; Fetus - abnormalities; Genetic Testing; Homozygote; Humans; Infant, Newborn; Kinesin - genetics; Liver - abnormalities; Male; Mutation; Oligonucleotide Array Sequence Analysis; Pancreas - abnormalities; Pathology; Polycystic Kidney Diseases - genetics; Polycystic Kidney Diseases - pathology; Polymorphism, Single Nucleotide; Pregnancy
• ISSN: 1525-1578; 1943-7811
• DOI: 10.2353/jmoldx.2010.090033

We have investigated a family where two siblings had a developmental disorder associated with polycystic dysplastic kidney disease that was incompatible with postnatal survival. Additional features observed were ductal plate malformation in the liver, dysplasia of the pancreas, and (in one individual) complete situs inversus and polymicrogyria of the cingulate gyri. The autopsy findings were compatible with renal-hepatic-pancreatic dysplasia, a condition with unknown genetic cause at the time of autopsy but with similarities to the Meckel-Gruber/Joubert group of recessive ciliopathies. Consanguinity between the parents made it likely that the mutated gene (with known or potential function in cilia) was located within a rather large region of homozygosity in the affected individuals (identical by descent). Using genetic markers (50K single nucleotide polymorphism microarrays), we found a single large homozygous region of 21.16 Mb containing ∼200 genes on the long arm of chromosome 3. This region contained two known ciliopathy genes: NPHP3 (adolescent nephronophthisis) and IQCB1 ( NPHP5 ), which is associated with Senior-Löken syndrome. In NPHP3 , homozygosity for a deletion of the conserved splice acceptor dinucleotide (AG) preceding exon 20 was found. Our finding confirms the recent report that NPHP3 -null mutations cause renal-hepatic-pancreatic dysplasia. Also, our case illustrates that genes for rare and genetically heterogeneous recessive conditions may be identified by homozygosity mapping using single nucleotide polymorphism arrays in the routine clinical setting.