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.

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

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

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.

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