Ruxandra Neatu

Key Points: Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods: We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8 / ALG9 pathogenic variants. Results: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare. Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

Introduction: Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis. Methods: Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines. We performed a bespoke reanalysis of Whole Genome Sequencing (WGS) data and coupled this with revised phenotypic data and targeted PCR and Sanger sequencing to provide a precise molecular genetic diagnosis. Results: We detected a heterozygous PKD1 frameshift variant within the WGS data which segregated with the redefined ADPKD phenotypes. An additional heterozygous exon deletion in ALG8 was also found in affected and unaffected individuals, but its precise clinical significance remains unclear. Conclusion: This case illustrates that reanalysis of WGS data in unsolved cases of cystic kidney disease is valuable. Clinical phenotypes must be reassessed as these may have been incorrectly recorded and evolve over time. Undertaking additional studies including genotype-phenotype correlation in wider family members provides useful diagnostic information.

LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps with the recently annotated lncRNA AC061979.1, a 1712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression pattern of the transcript, we processed 3.9 TBases of publicly available RNA-SEQ data across 27 independent studies involving lung airway epithelial cells. Epithelial lung cells showed expression of this putative pancRNA. The findings were independently validated in cell lines and primary cells. The rs35705950 is found within a conserved region (from fish to primates) within the expressed sequence indicating functional importance. These results implicate the rs35705950-containing AC061979.1 pancRNA as a novel component of the MUC5B expression control minicircuitry.