Clinical Utility of Genetic Testing with Geographical Locations in ADPKD: Describing New Variants.

Background: Our study aims to comment on all ADPKD variants identified in our health area and explain how they are distributed geographically, to identify new variants, and relate the more frequent variants with their renal phenotype in terms of kidney survival. Materials and Methods: We identified patients suffering from ADPKD in a specialized consultation unit; genealogical trees were constructed from the proband. According to the ultrasound-defined modified Ravine-Pei criteria, relatives classified as at risk were offered participation in the genetic study. Socio-demographic, clinical, and genetic factors related to the impact of the variant on the survival of the kidney and the patient, such as age at RRT beginning and age of death, were recorded. Results: In 37 families, 33 new variants of the PKD1 gene were identified, which probably produce a truncated protein. These variants included 2 large deletions, 19 frameshifts, and 12 stop-codons, all of which had not been previously described in the databases. In 10 families, six new probably pathogenic variants in the PKD2 gene were identified. These included three substitutions; two deletions, one of which was intronic and not associated with any family; and one duplication. A total of 11 missense variants in the PKD1 gene were grouped in 14 families and classified as probably pathogenic. We found that 33 VUS were grouped into 18 families and were not described in the databases, while another 15 were without grouping, and there was only 1 in the PKD2 gene. Some of these variants were present in patients with a different pathogenic variant (described or not), and the variant was probably benign. Renal survival curves were compared to nonsense versus missense variants on the PKD1 gene to check if there were any differences. A group of 328 patients with a nonsense variant was compared with a group of 264 with a missense variant; mean renal survival for truncated variants was lower (53.1 ± 0.46 years versus non-truncated variant 59.1 ± 1.36 years; Log Rank, Breslow, and Tarone Ware, p < 0.05). Conclusions: To learn more about ADPKD, it is necessary to understand genetics. By describing new genetic variants, we are approaching creation of an accurate genetic map of the disease in our country, which could have prognostic and therapeutic implications in the future.

Erratum to: Founding mutations explains hotspots of polycystic kidney disease in Southern Spain.

[This corrects the article DOI: 10.1093/ckj/sfaa261.].

Founding mutations explains hotspots of polycystic kidney disease in Southern Spain.

Our group identified two pathogenic variants on the PKD1 gene, c.10527_10528delGA and c.7292T>A, from unrelated families. They came from two small counties in Granada, with 61 and 26 autosomal dominant polycystic kidney disease (ADPKD) individuals affected. To determine a common ancestor, healthy and ADPKD individuals from these families were genotyped by analysing four microsatellites located on chromosome 16. Our study identified a common haplotype in all ADPKD individuals. These findings underpin our hypothesis of the founder effect and explain why there is a high frequency of ADPKD in small regions. Determining hotspots of ADPKD will help to better plan healthcare in the future.

Nueva mutación asociada a poliquistosis renal autosómica dominante con efecto fundador localizada en la Alpujarra de Granada / New mutation associated with autosomal dominant polycystic kidney disease with founder effect located in the alpujarra region of granada

OBJETIVO: Demostrar que la variante no descrita en el gen PKD1 c.7292T>A, identificada en cuatro familias de la comarca de la Alpujarra de Granada, es la causante de la poliquistosis renal autosómica dominante (PQRAD). Esta variante consiste en una sustitución transversión de timina (T) por adenina (A) que a nivel de la proteína policistina 1 produce un cambio de leucina (Leu/L) por glutamina (Gln/Q) en la posición 2431 (p.Leu2431Gln). MÉTODO: Registramos variables sociodemográficas y clínicas a través de la realización de historias clínicas, árboles genealógicos, ecografías y estudios genéticos a individuos afectos y sanos pertenecientes a estas familias en el contexto del estudio de segregación. RESULTADOS: Todos los individuos afectados portaban en heterocigosis la variante c.7292T>A, mientras que los individuos sanos no la portaron. En las familias estudiadas, el 62,9% eran mujeres. El diagnóstico de PQRAD se realizó a los 29,3 ± 15,82 años de edad, después de haber tenido el primer hijo en el 64,8%. Los motivos principales de diagnóstico de la enfermedad fueron antecedentes familiares y episodios de hematuria. El inicio de tratamiento renal sustitutivo (TRS) se produjo a la edad de 55,8 ± 7,62 años (rango 44-67), y el éxitus a los 63 ± 92,2 años (rango 48-76), siendo la causa desconocida, cardiovascular e insuficiencia renal las más frecuentes; la mediana de supervivencia renal se estableció a los 58,5 ± 0,77 años y la mediana de supervivencia del paciente a los 67 ± 3,54 años. No observamos diferencias en la supervivencia del riñón y del paciente según el sexo. De los pacientes fallecidos, el 52,2% necesitaron TRS y el 94,4% tenían algún grado de insuficiencia renal (IR). CONCLUSIONES: La variante c.7292T>A en el gen PKD1 es responsable de la enfermedad y su distribución en la comarca de la Alpujarra de Granada sugiere un efecto fundador. En la PQRAD es necesario realizar estudios de segregación que ayuden a reclasificar variantes genéticas, en este caso de indeterminada a patogénica

OBJECTIVE: To demonstrate that the variant not described in PKD1 gene c.7292T> A, identified in four families from the Alpujarra in Granada, is the cause of autosomal dominant polycystic kidney disease (ADPKD). This variant consists of a transversion of thymine (T) by adenine (A) that at the level of the Polycystin 1 protein produces a change of leucine (Leu / L) by Glutamine (Gln / Q) in position 2431 (p.Leu2431Gln). METHOD: Sociodemographic and clinical variables were registered using clinical histories, genealogical trees, ultrasounds and genetic analysis to ADPKD and healthy individuals belonging to these families in the context of segregation study. RESULTS: All PKD individuals carried the c.7292T>A variant in heterozygosis, whereas healthy ones did not. Among all ADPKD patients, 62.9% were women. ADPKD diagnosis was made at 29.3 ± 15.82 years, after having the first child in 64.8%. The main reasons for diagnosis were family history and hematuria episodes. The onset of renal replacement therapy (RRT) occurred at 55.8 ± 7.62 years (range 44-67), and death at 63 ± 92.2 years (range 48-76), being the cause unknown, cardiovascular and insufficiency kidney the most frequent; the median of renal survival was established at 58.5 ± 0.77 years and the median survival of patients at 67.2 ± 3.54 years. No differences in kidney and patient survivals were observed according to sex. Among deceased patients, 52.2% required RRT and 94.4% suffered from renal failure. CONCLUSIONS: The variant c.7292T>A in PKD1 gene is responsible for the disease, and its distribution in the Alpujarra region of Granada suggests a founder effect. In ADPKD it is necessary to perform segregation studies that help us to reclassify genetic variants, in this case from indeterminate to pathogenic

New mutation associated with autosomal dominant polycystic kidney disease with founder effect located in the alpujarra region of granada. / Nueva mutación asociada a poliquistosis renal autosómica dominante con efecto fundador localizada en la Alpujarra de Granada.

OBJECTIVE: To demonstrate that the variant not described in PKD1 gene c.7292T> A, identified in four families from the Alpujarra in Granada, is the cause of autosomal dominant polycystic kidney disease (ADPKD). This variant consists of a transversion of thymine (T) by adenine (A) that at the level of the Polycystin 1 protein produces a change of leucine (Leu / L) by Glutamine (Gln / Q) in position 2431 (p.Leu2431Gln). METHOD: Sociodemographic and clinical variables were registered using clinical histories, genealogical trees, ultrasounds and genetic analysis to ADPKD and healthy individuals belonging to these families in the context of segregation study. RESULTS: All PKD individuals carried the c.7292T>A variant in heterozygosis, whereas healthy ones did not. Among all ADPKD patients, 62.9% were women. ADPKD diagnosis was made at 29.3 ± 15.82 years, after having the first child in 64.8%. The main reasons for diagnosis were family history and hematuria episodes. The onset of renal replacement therapy (RRT) occurred at 55.8 ± 7.62 years (range 44-67), and death at 63 ± 92.2 years (range 48-76), being the cause unknown, cardiovascular and insufficiency kidney the most frequent; the median of renal survival was established at 58.5 ± 0.77 years and the median survival of patients at 67.2 ± 3.54 years. No differences in kidney and patient survivals were observed according to sex. Among deceased patients, 52.2% required RRT and 94.4% suffered from renal failure. CONCLUSIONS: The variant c.7292T>A in PKD1 gene is responsible for the disease, and its distribution in the Alpujarra region of Granada suggests a founder effect. In ADPKD it is necessary to perform segregation studies that help us to reclassify genetic variants, in this case from indeterminate to pathogenic.

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients.

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.

Overview of autosomal dominant polycystic kidney disease in the south of Spain. / Panorámica de la poliquistosis renal autosómica dominante en una región del sur de España.

INTRODUCTION: Although autosomal dominant polycystic kidney disease is the most common hereditary kidney disease, available data tend to be limited to after initiation of renal replacement therapy. OBJECTIVE: To ascertain an overview of autosomal dominant polycystic kidney disease within the health area of Granada in southern Spain. MATERIAL AND METHODS: From January 2007 to December 2016, we collected clinical, family and demographic information about all patients with autosomal dominant polycystic kidney disease, irrespective of whether or not they were treated with RRT, in the Granada health area. The computer software SPSS 15.0 and GenoPro were used. RESULTS: 50.6% of the 1,107 diagnosed patients were men. 99.1% were Caucasian and 4-6 generations/family were studied. The geographical distribution was heterogeneous. There was no family history in 2.43%. The mean age of diagnosis was 34.0±17.80 years and the diagnosis was made after having offspring in 57.7% of cases. The main reason for diagnosis was family history (46.4%). The mean age of initiation of renal replacement therapy was 54.2±11.05 years. 96.3% of the deceased had some degree of renal failure at the time of death. The mean age of death was 60.9±14.10 years, the main cause of death being unknown in 33.5% of cases, followed by cardiovascular (27.8%). CONCLUSIONS: Cases and families were concentrated in certain geographical areas and a significant number of individuals were undiagnosed prior to cardiovascular death or diagnosed late after reproduction. Given that there is currently no curative treatment, the primary prevention strategy of preimplantation genetic diagnosis should play a leading role.