Mohamed H Al-Hamed1, Nada Alsahan2, Sarah J Rice3, Noel Edwards3, Eman Nooreddeen4, Maha Alotaibi5, Wesam Kurdi2, Maha Alnemer2, Naderah Altaleb1, Wafa Ali1, Nouf Al-Numair1, Najd Almejaish4, John A Sayer3,6, Faiqa Imtiaz7. 1. Department of Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia. 2. Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia. 3. Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, UK. 4. Paediatric Nephrology Department, National Guard Hospital, Almadinah almonawarah, Saudi Arabia. 5. Division of Genetics & Metabolic, King Saud Medical City, Riyadh, Saudi Arabia. 6. NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, NE4 5PL, UK. 7. Department of Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia. fahmad@kfshrc.edu.sa.
Abstract
BACKGROUND: Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. METHODS: Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients. RESULTS: In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. CONCLUSIONS: Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.
BACKGROUND:Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. METHODS: Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKDpatients. RESULTS: In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. CONCLUSIONS: Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.
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