Case Report Whole-exome analysis of a child with polycystic kidney disease and ventriculomegaly

Abstract

ABSTRACT. Autosomal recessive polycystic kidney disease (ARPKD)is an inherited ciliopathy leading to progressive kidney and liver disease. Biallelic mutations in the PKHD1 gene underlie this condition. We describe a child with bilaterally enlarged cystic kidneys, portal hypertension, and cerebral ventriculomegaly. Molecular genetic investigations using whole-exome sequencing and confirmation using Sanger sequencing revealed a homozygous pathogenic mutation in PKHD1 underlying the clinical phenotype of ARPKD. Whole-exome data analysis was used to search for additional rare variants in additional ciliopathy genes that may have contributed to the unusual brain phenotype. Aside from a rare hypomorphic allele in MKS1, no other pathogenic variants were detected. 3619Polycystic kidney disease and ventriculomegaly ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 3618-3624 (2015) We conclude that the homozygous pathogenic mutation in PKHD1 underlies the ciliopathy phenotype in this patient.

Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by sanger sequencing and MLPA analysis

“…In the past years, some PKHD1 mutations were identified by exome sequencing. 23,30,31 Recently, Tavira et al 51 estimated that the cost of the NGS of the 30 samples, plus Sanger sequencing of PCR-fragments to assign the identified mutations, was ∼ 3.5-fold lower than the Sanger sequencing of all the PKHD1 amplicons on an ABI3130xl sequencer. Besides, Sanger sequencing-based molecular screening would have required several weeks, whereas the NGS project was completed in only 2 weeks.…”

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…familial Mediterranean fever (MEFV gene) [120], thiamine-responsive megaloblastic anemia (SLC19A2 gene) [121], cerebellar atrophy and developmental delay (PLA2G6, KIF1A and MOCS2A genes) [122], micro-/anophthalmia (VSX2, SOX2, and FOXE3 genes) [123], RAGdeficiency (RAG1 and RAG2 genes) [124], auriculocondylar syndrome (PLCB4, GNAI3, and EDN1 genes) [125], ectodermal dysplasia (EDA, EDAR, and EDARADD genes) [126], 3phosphoglycerate dehydrogenase deficiency (PHGDH gene) [127], carpenter syndrome (RAB23 gene) [128], disorders/differences of sex development (NR5A1, CYP19A1, AMH, AMHR2, WT1, HHAT, and FANCA and in the X-linked genes KDM6A and ARX genes) [129] and autosomal recessive polycystic kidney disease (PKHD1 gene) [130]. WES studies in Iraqi people revealed associated genes of epileptic encephalopathy (SLC13A5 gene) [131],…”

“…Studies (WES) in Egyptian individuals revealed associated genes of primary hyperoxaluria type I ( AGXT gene), infantile hypercalcemia/hypophosphatemia/nephrolithiasis ( SLC34A1 gene) [ 115 ], severe combined immunodeficiency ( JAK3 gene) [ 116 ], propionic acidemia ( PCCA gene) [ 117 ], sulfite oxidase deficiency ( SUOX gene), molybdenum cofactor deficiency ( MOCS2 gene) [ 118 ], primary hereditary microcephaly ( ASPM gene) [ 119 ], familial Mediterranean fever ( MEFV gene) [ 120 ], thiamine-responsive megaloblastic anemia ( SLC19A2 gene) [ 121 ], cerebellar atrophy and developmental delay ( PLA2G6 , KIF1A and MOCS2A genes) [ 122 ], micro-/anophthalmia ( VSX2 , SOX2 , and FOXE3 genes) [ 123 ], RAG-deficiency ( RAG1 and RAG2 genes) [ 124 ], auriculocondylar syndrome ( PLCB4 , GNAI3 , and EDN1 genes) [ 125 ], ectodermal dysplasia ( EDA , EDAR , and EDARADD genes) [ 126 ], 3-phosphoglycerate dehydrogenase deficiency ( PHGDH gene) [ 127 ], Carpenter syndrome ( RAB23 gene) [ 128 ], disorders/differences of sex development (NR5A1, CYP19A1, AMH, AMHR2, WT1, HHAT, and FANCA and in the X-linked genes KDM6A and ARX genes) [ 129 ] and autosomal recessive polycystic kidney disease ( PKHD1 gene) [ 130 ]. WES studies in Iraqi people revealed associated genes of epileptic encephalopathy ( SLC13A5 gene) [ 131 ], juvenile neuronal ceroid lipofuscinoses ( CLN3 gene) [ 132 ], inherited thrombocytopenia ( FYB gene) [ 133 ], microcephaly ( TMX2 gene) [ 134 ], non-syndromic retinal dystrophy ( POC1B gene) [ 135 ], progressive pseudorheumatoid dysplasia ( WISP3 gene) [ 136 ], dedicator of cytokinesis 8 deficiency ( DOCK8 gene) [ 137 ], and developmental delay ( MED27 gene) [ 138 ].…”