Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective.

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Diagnostic Yield of Exome Sequencing in Early-Onset Hypertensive Nephropathy in Adults.

INTRODUCTION: Hypertensive nephrosclerosis (HN) ranks as one of the most frequent causes of chronic kidney disease (CKD), but its very existence has repeatedly been called into question, especially in young adults. Its diagnostic framework is established chiefly on non-specific clinical criteria, and its defining histopathological set of features is in fact shared by numerous other conditions. Genetic testing based on exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in timely fashion in nephrology, with a significant number of re-established diagnoses. The aim of this study was to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD: Since September 2018, ES has been readily available as part of the routine diagnostic work-up in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e., <45 years old). We retrospectively collected the ES data performed in the context of hypertensive nephropathy in our institution between September 2018 and February 2021. RESULTS: A total of 128 patients were sequenced in the context of hypertensive nephropathy with early onset. The chief indications of ES were an early onset of CKD (47%), family history of kidney disease (8%), or both (18%). We detected diagnostic variants in 19 of the 128 patients (15%), encompassing a total of 13 different monogenic disorders. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 7 vs. 30% in non-African ancestry patients, p < 0.001). CONCLUSIONS: The high diagnostic yield of ES (15%) in a population of patients thought to have HN casts further doubts on the validity of the existing diagnosis criteria, including histological criteria, supposed to characterize the condition. This was especially true in patients with no African ancestry, where ES positivity reached 30%.

Can we identify patients carrying targeted deleterious DPYD variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.

OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches. METHODS: This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022). RESULTS: Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3 % of patients were partially deficient (U 16-150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U. CONCLUSIONS: These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency.

Beyond the kidney biopsy: genomic approach to undetermined kidney diseases.

Background: According to data from large national registries, almost 20%-25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. Methods: ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. Results: We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded, respectively, the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES "first" eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (P = .02) and in patients with a family history of kidney disease (P < .0001), reaching 56.8% when the patient had both first- and second-degree family history of renal disease. Conclusion: Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome "first" may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

Corrigendum to "Atypical Clinical Presentation of Autosomal Recessive Polycystic Kidney Mimicking Medullary Sponge Kidney Disease" [Kidney International Reports Volume 7, Issue 4, April 2022, Pages 916-919].

[This corrects the article DOI: 10.1016/j.ekir.2021.11.035.].