Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-hypoperistalsis-syndrome (MMIHS) is a rare and early-onset congenital disease characterized by massive abdominal distension due to a large non-obstructive bladder, a microcolon and decreased or absent intestinal peristalsis. While in most cases inheritance is autosomal dominant and associated with heterozygous variant in ACTG2 gene, an autosomal recessive transmission has also been described including pathogenic bialellic loss-of-function variants in MYH11. We report here a novel family with visceral myopathy related to MYH11 gene, confirmed by whole genome sequencing (WGS). WGS was performed in two siblings with unusual presentation of MMIHS and their two healthy parents. The 38 years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30 years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus. WGS was completed by retrospective digestive pathological analyses. Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2 Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578_2580del, p.Glu860del inherited from the mother. Pathology analyses of the colon and the rectum revealed structural changes which significance of which is discussed. Cardiac and vascular assessment of the mother was normal. This is the second report of a visceral myopathy corresponding to late-onset form of MMIHS related to compound heterozygosity in MYH11; with complete gene deletion and a hypomorphic allele in trans. The hypomorphic allele harbored by the mother raised the question of the risk of aortic disease in adults. This case shows the interest of WGS in deciphering complex phenotypes, allowing adapted diagnosis and genetic counselling.

Performance and clinical utility of a new supervised machine-learning pipeline in detecting rare ciliopathy patients based on deep phenotyping from electronic health records and semantic similarity.

BACKGROUND: Rare diseases affect approximately 400 million people worldwide. Many of them suffer from delayed diagnosis. Among them, NPHP1-related renal ciliopathies need to be diagnosed as early as possible as potential treatments have been recently investigated with promising results. Our objective was to develop a supervised machine learning pipeline for the detection of NPHP1 ciliopathy patients from a large number of nephrology patients using electronic health records (EHRs). METHODS AND RESULTS: We designed a pipeline combining a phenotyping module re-using unstructured EHR data, a semantic similarity module to address the phenotype dependence, a feature selection step to deal with high dimensionality, an undersampling step to address the class imbalance, and a classification step with multiple train-test split for the small number of rare cases. The pipeline was applied to thirty NPHP1 patients and 7231 controls and achieved good performances (sensitivity 86% with specificity 90%). A qualitative review of the EHRs of 40 misclassified controls showed that 25% had phenotypes belonging to the ciliopathy spectrum, which demonstrates the ability of our system to detect patients with similar conditions. CONCLUSIONS: Our pipeline reached very encouraging performance scores for pre-diagnosing ciliopathy patients. The identified patients could then undergo genetic testing. The same data-driven approach can be adapted to other rare diseases facing underdiagnosis challenges.

Post-obstructive diuresis after posterior urethral valve treatment in neonates: a retrospective cohort study.

BACKGROUND: The management of posterior urethral valve (PUV) in neonates requires close monitoring in the intensive care unit because of the risk of post-obstructive diuresis (POD). Our aim was to describe the incidence and factors associated with POD in newborns treated for PUV. METHODS: Retrospective analysis of the medical records of all neonates who underwent surgical intervention for PUV in our neonatal intensive care unit between January 2014 and April 2021. RESULTS: Of the 40 patients included, 15 (37.5%) had POD defined by urine output > 6 ml.kg-1.h-1 during the first 24 h following urinary tract obstruction relief. At prenatal ultrasound examinations, oligohydramnios was more common in the group with POD than in the group without (53.3% vs. 8%, p = 0.002). Preterm birth was more frequent in neonates with POD (66.7% vs. 8%; p < 0.001). Median serum creatinine (212 [137-246] vs. 95 [77-125] µmol.l-1; p < 0.001) and urea (8.5 [5.2-12.2] vs. 4.1 [3.5-4.7] mmol.l-1; p < 0.001) concentrations on the day of obstruction relief were significantly higher in the group with POD than in the group without. After adjustment for prematurity, logistic regression models confirmed correlation between the occurrence of POD and the severity of the consequences of urethral obstruction (i.e., oligohydramnios and serum creatinine levels; ß = 2.90 [0.88; 5.36], p = 0.013 and ß = 0.014 [0.003; 0.031], p = 0.034, respectively). CONCLUSIONS: In neonates, POD is common after the relief of PUV-related obstruction. Our findings may help to identify patients at highest risk. A higher resolution version of the Graphical abstract is available as Supplementary information.

VNtyper enables accurate alignment-free genotyping of MUC1 coding VNTR using short-read sequencing data in autosomal dominant tubulointerstitial kidney disease.

The human genome comprises approximately 3% of tandem repeats with variable length (VNTR), a few of which have been linked to human rare diseases. Autosomal dominant tubulointerstitial kidney disease-MUC1 (ADTKD-MUC1) is caused by specific frameshift variants in the coding VNTR of the MUC1 gene. Calling variants from VNTR using short-read sequencing (SRS) is challenging due to poor read mappability. We developed a computational pipeline, VNtyper, for reliable detection of MUC1 VNTR pathogenic variants and demonstrated its clinical utility in two distinct cohorts: (1) a historical cohort including 108 families with ADTKD and (2) a replication naive cohort comprising 2,910 patients previously tested on a panel of genes involved in monogenic renal diseases. In the historical cohort all cases known to carry pathogenic MUC1 variants were re-identified, and a new 25bp-frameshift insertion in an additional mislaid family was detected. In the replication cohort, we discovered and validated 30 new patients.

A wave of deep intronic mutations in X-linked Alport syndrome.

X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing. Bulk RNAseq and/or targeted RNAseq using a capture panel of kidney genes was performed. Alternative splicing events were compared to those of 15 controls by a developed bioinformatic score. When using targeted RNAseq, COL4A5 coverage was found to be 23-fold higher than with bulk RNASeq and revealed 30 significant alternative splicing events in 17 of the 19 patients. After computational scoring, a pathogenic transcript was found in all patients. A causative variant affecting COL4A5 splicing and absent in the general population was identified in all cases. Altogether, we developed a simple and robust method for identification of aberrant transcripts due to pathogenic deep-intronic COL4A5 variants. Thus, these variants, potentially targetable by specific antisense oligonucleotide therapies, were found in a high percentage of patients with XLAS in whom pathogenic variants were missed by conventional DNA sequencing.

The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies.

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension.

BACKGROUND: Early-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger children and neonates. We investigated the genetic bases of early-onset isolated systemic hypertension. METHODS: Whole-exome sequencing (WES) was followed by variant filtering and Sanger sequencing for validation and familial segregation of selected variants in a large consanguineous family. mRNA expression was performed to evaluate the impact of the predicted pathogenic variant on gene expression. WES or Sanger sequencing was performed in additional unrelated affected individuals. RESULTS: In one consanguineous family with four children presenting with isolated neonatal-onset systemic hypertension, we identified homozygous stop-gain variant in the NPR1 gene (NM_000906.4:c.1159C>T (p.Arg387Ter)) in the affected individuals. This variant leads to a dramatic reduction of NPR1 RNA levels. NPR1 gene analysis of additional families allowed the identification of another family with two affected children carrying homozygous frameshift variant in NPR1 (NM_000906.4:c.175del (p.Val59TrpfsTer8)). CONCLUSION: We show for the first time that biallelic loss of function of NPR1 is responsible for isolated neonatal-onset systemic hypertension in humans, which represents a new autosomal recessive genetic cause of infantile systemic hypertension or cardiogenic shock. This is consistent with studies reporting early-onset systemic hypertension and sudden death in Npr1-deficient mice. NPR1 gene analysis should be therefore investigated in infants with early-onset systemic hypertension with or without cardiogenic shock of unknown origin.

[Major advances in pediatric nephro-genetics]. / Les grandes avancées en néphro-génétique pédiatrique.

The rise of genetics in the last decades has allowed major advances in the understanding of the mechanisms leading to inherited kidney diseases. From the first positional cloning studies to the advent of high-throughput sequencing (NGS), genome analysis technologies have become increasingly efficient, with an extraordinary level of resolution. Moreover, sequencing prices have decreased from one million dollars for the sequencing of James Watson's genome in 2008, to a few hundred dollars for the sequencing of a genome today. Thus, molecular diagnosis has a central place in the diagnosis of these patients and influences the therapeutic management in many situations. However, although NGS is a powerful tool for the identification of variants involved in diseases, it also exposes to the risk of over-interpretation of certain variants, leading to erroneous diagnoses, requiring the use of specialists. In this review, we first propose a brief retrospective of the essential steps that led to the current knowledge and the development of NGS for the study of hereditary nephropathies in children. This review is then an opportunity to present the main hereditary nephropathies and the underlying molecular mechanisms. Among them, we emphasize ciliopathies, congenital anomalies of the kidney and urinary tract, podocytopathies and tubulopathies.

Title: Les grandes avancées en néphro-génétique pédiatrique. Abstract: L'essor de la génétique au cours des dernières décennies a permis des avancées majeures dans la compréhension des mécanismes conduisant aux maladies rénales héréditaires. Des premières études par clonage positionnel jusqu'à l'avènement du séquençage à haut débit (NGS), les techniques d'analyse du génome sont devenues de plus en plus performantes, avec un niveau de résolution extraordinaire. Les prix de séquençage se sont effondrés, passant d'un million de dollars (environ 940 millions d'euros) pour le séquençage du génome de James Watson en 2008, à quelques centaines d'euros pour le séquençage d'un génome aujourd'hui. Le diagnostic moléculaire tient ainsi une place centrale pour le diagnostic des patients et influe sur la prise en charge thérapeutique dans de nombreuses situations. Mais si le NGS est un outil performant pour l'identification de variants impliqués dans les maladies, il expose au risque de surinterprétation de certains variants, conduisant à des diagnostics erronés. Dans cette revue, nous proposons une brève rétrospective des étapes essentielles qui ont conduit aux connaissances actuelles et au développement du NGS pour l'étude des néphropathies héréditaires de l'enfant. Nous développerons ensuite les principales néphropathies héréditaires et les mécanismes moléculaires sous-jacents.

Overcoming the challenges associated with identification of deep intronic variants by whole genome sequencing.

Whole-genome sequencing (WGS) now allows identification of multiple variants in non-coding regions. The large number of variants identified by WGS however complicates their interpretation. Through identification of the first deep intronic variant in NPHS2, which encodes podocin, a protein implicated in autosomal recessive steroid resistant nephrotic syndrome (SRNS), we compare herein three different tools including a newly developed targeted NGS-based RNA-sequencing to explore the splicing effect of intronic variations. WGS identified two different variants in NPHS2 eventually involved in the disease. Through RT-PCR, exon-trapping Minigene assay and targeted RNA sequencing, we were able to identify the splicing defect in NPHS2 mRNA from patient kidney tissue. Only targeted RNA-seq simultaneously analyzed the effect of multiple variants and offered the opportunity to quantify consequences on splicing. Identifying deep intronic variants and their role in disease is of utmost importance. Alternative splicing can be predicted by in silico tools but always requires confirmation through functional testing with RNA analysis from the implicated tissue remaining the gold standard. When several variants with potential effects on splicing are identified by WGS, a targeted RNA sequencing panel could be of great value.

Bi-allelic pathogenic variants in ITGA8 cause slowly progressive renal disease of unknown etiology.

Integrin Subunit Alpha 8 gene (ITGA8) encodes an integrin chain that is known to be critical in the early stage of the kidney development. Bi-allelic pathogenic variants in ITGA8 are associated with bilateral renal agenesis, as well as anomalies involving urogenital system. Here, we report two unrelated patients presenting with slowly progressing chronic kidney disease associated with bilateral renal hypodysplasia carrying homozygous loss of function variants in the ITGA8 gene. These results broaden the clinical and genotypic spectrum of ITGA8 defects, revealing the high and unexpected degree of phenotypic heterogeneity of this autosomal recessive disease. Our study emphasizes the usefulness of Next-Generation Sequencing in unraveling the genetic cause of chronic kidney disease of unknown etiology, and raises the question of genetic modifiers involved in the variation of the phenotypes associated with autosomal recessive ITGA8 pathogenic variants.

Definition, diagnosis and clinical management of non-obstructive kidney dysplasia: a consensus statement by the ERKNet Working Group on Kidney Malformations.

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.

Targeted next-generation sequencing in a large series of fetuses with severe renal diseases.

We report the screening of a large panel of genes in a series of 100 fetuses (98 families) affected with severe renal defects. Causative variants were identified in 22% of cases, greatly improving genetic counseling. The percentage of variants explaining the phenotype was different according to the type of phenotype. The highest diagnostic yield was found in cases affected with the ciliopathy-like phenotype (11/15 families and, in addition, a single heterozygous or a homozygous Class 3 variant in PKHD1 in three unrelated cases with autosomal recessive polycystic kidney disease). The lowest diagnostic yield was observed in cases with congenital anomalies of the kidney and urinary tract (9/78 families and, in addition, Class 3 variants in GREB1L in three unrelated cases with bilateral renal agenesis). Inheritance was autosomal recessive in nine genes (PKHD1, NPHP3, CEP290, TMEM67, DNAJB11, FRAS1, ACE, AGT, and AGTR1), and autosomal dominant in six genes (PKD1, PKD2, PAX2, EYA1, BICC1, and MYOCD). Finally, we developed an original approach of next-generation sequencing targeted RNA sequencing using the custom capture panel used for the sequencing of DNA, to validate one MYOCD heterozygous splicing variant identified in two male siblings with megabladder and inherited from their healthy mother.

Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice.

The overall diagnostic yield of massively parallel sequencing-based tests in patients with chronic kidney disease (CKD) is 30% for paediatric cases and 6-30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients. However, in reality, several barriers appear to hinder the implementation of massively parallel sequencing-based diagnostics in routine clinical practice. In this article we aim to support the nephrologist to overcome these barriers. After a detailed discussion of the general items that are important to genetic testing in nephrology, namely genetic testing modalities and their indications, clinical information needed for high-quality interpretation of genetic tests, the clinical benefit of genetic testing and genetic counselling, we describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin.

Extracorporeal Shockwave Lithotripsy for Cystine Stones in Children: An Observational, Retrospective, Single-Center Analysis.

Purpose: Cystinuria is a genetic disorder characterized by a defective reabsorption of cystine and dibasic amino acids leading to development of urinary tract calculi from childhood onward. Cystine lithiasis is known to be resistant to fragmentation. The aim was to evaluate our long-term experience with extracorporeal shockwave lithotripsy (ESWL) used as first-line urological treatment to treat cystine stones in children. Methods: We retrospectively reviewed the charts of all children who underwent ESWL for cystine stone. We assessed the 3-month stone-free rate, according to age, younger (group 1) or older (group 2) than 2 years old. Results: Between 2003 and 2016, 15 patients with a median (IQR) age at first treatment of 48 (15-108) months underwent ESWL in monotherapy. Median age was, respectively, 15 and 108 months in each group. The median (IQR) stone burden was 2,620 (1,202-8,265) mm3 in group I and 4,588 (2,039-5,427) mm3 in group II (p = 0.96). Eleven patients had bilateral calculi. ESWL was repeated on average 2.4 times, with a maximum of 4 for patients of group I, and 4.8 times, with a maximum of 9 for group II (p > 0.05). ESWL in monotherapy was significantly more efficient to reach stone-free status for children under 2 years of age: 83% vs. 6.2% (p = 0.040). The median (IQR) follow-up of the study was 69 (42-111) months. Conclusion: ESWL appears as a valid urological option for the treatment of cystine stones, in young children. Even if cystine stones are known to be resistant to fragmentation, we report 83% of stone-free status at 3 months with ESWL used in monotherapy in children under 2 years old with cystinuria. In older children, the success rate is too low to recommend ESWL as a first line approach.

The European Rare Kidney Disease Registry (ERKReg): objectives, design and initial results.

BACKGROUND: The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient's outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically. RESULTS: Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases. CONCLUSIONS: ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.

Cystic kidney diseases associated with mutations in phosphomannomutase 2 promotor: a large spectrum of phenotypes.

BACKGROUND: Co-occurrence of polycystic kidney disease and hyperinsulinemic hypoglycemia has been reported in children in a few families associated with a variant in the promotor of the PMM2 gene, at position -167 upstream of the coding sequence. PMM2 encodes phosphomannomutase 2, a key enzyme in N-glycosylation. While biallelic coding PMM2 mutations are involved in congenital disorder of glycosylation CDG1A, that particular variant in the promoter of the gene, either in the homozygous state or associated with a mutation in the coding exons of the gene, is thought to restrict the N-glycosylation defect to the kidney and the pancreas. METHODS: Targeted exome sequencing of a panel of genes involved in monogenic kidney diseases. RESULTS: We identified a PMM2 variant at position -167 associated with a pathogenic PMM2 variant in the coding exons in 3 families, comprising 6 cases affected with a cystic kidney disease. The spectrum of phenotypes was very broad, from extremely enlarged fetal cystic kidneys in the context of a COACH-like syndrome, to isolated cystic kidney disease with small kidneys, slowly progressing toward kidney failure in adulthood. Hypoglycemia was reported only in one case. CONCLUSION: These data show that the PMM2 promotor variation, in trans of a PMM2 coding mutation, is associated with a wide spectrum of kidney phenotypes, and is not always associated with extra-renal symptoms. When present, extra-renal defects may include COACH-like syndrome. These data prompt screening of PMM2 in unresolved cases of fetal hyperechogenic/cystic kidneys as well as in cystic kidney disease in children and adults. Graphical Abstract.

Cystinuria: clinical practice recommendation.

Cystinuria (OMIM 220100) is an autosomal recessive hereditary disorder in which high urinary cystine excretion leads to the formation of cystine stones because of the low solubility of cystine at normal urinary pH. We developed clinical practice recommendation for diagnosis, surgical and medical treatment, and follow-up of patients with cystinuria. Elaboration of these clinical practice recommendations spanned from June 2018 to December 2019 with a consensus conference in January 2019. Selected topic areas were chosen by the co-chairs of the conference. Working groups focusing on specific topics were formed. Group members performed systematic literature review using MEDLINE, drafted the statements, and discussed them. They included geneticists, medical biochemists, pediatric and adult nephrologists, pediatric and adult urologists experts in cystinuria, and the Metabolic Nephropathy Joint Working Group of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN members. Overall 20 statements were produced to provide guidance on diagnosis, genetic analysis, imaging techniques, surgical treatment (indication and modalities), conservative treatment (hydration, dietetic, alkalinization, and cystine-binding drugs), follow-up, self-monitoring, complications (renal failure and hypertension), and impact on quality of life. Because of the rarity of the disease and the poor level of evidence in the literature, these statements could not be graded. This clinical practice recommendation provides guidance on all aspects of the management of both adults and children with cystinuria, including diagnosis, surgery, and medical treatment.

Bi-allelic pathogenic variations in DNAJB11 cause Ivemark II syndrome, a renal-hepatic-pancreatic dysplasia.

DNAJB11 (DnaJ Heat Shock Protein Family (Hsp40) Member B11) heterozygous loss of function variations have been reported in autosomal dominant cystic kidney disease with extensive fibrosis, associated with maturation and trafficking defect involving both the autosomal dominant polycystic kidney disease protein polycystin-1 and the autosomal dominant tubulointerstitial kidney disease protein uromodulin. Here we show that biallelic pathogenic variations in DNAJB11 lead to a severe fetal disease including enlarged cystic kidneys, dilation and proliferation of pancreatic duct cells, and liver ductal plate malformation, an association known as Ivemark II syndrome. Cysts of the kidney were developed exclusively from uromodulin negative tubular segments. In addition, tubular cells from the affected kidneys had elongated primary cilia, a finding previously reported in ciliopathies. Thus, our data show that the recessive disease associated with DNAJB11 variations is a ciliopathy rather than a disease of the autosomal dominant tubulointerstitial kidney disease spectrum, and prompt screening of DNAJB11 in fetal hyperechogenic/cystic kidneys.