RESUMEN
There are two forms of diabetes insipidus, central (neurohypophyseal), and nephrogenic, caused by pathogenic variants in the AVP gene and the AVPR2 or AQP2 genes, respectively. We report on a four-generation family, seven individuals had central diabetes insipidus (CDI) and the female index patient seen from age 16 to 26 years had (mild) nephrogenic diabetes insipidus. In her father with CDI, a known pathogenic heterozygous AVP variant c.232_234del p.(Glu78del) was identified, confirming the diagnosis of CDI in him and the other affected family members. In the proband, molecular analysis disclosed a novel heterozygous AVPR2 gene variant, c.962A > T p.(Asn321Ile) and an extremely skewed X-inactivation, confirming X-linked nephrogenic diabetes insipidus (XL-NDI). Whole exome sequencing showed no further causative mutation. This is the first report on the co-existence of CDI and NDI in one family. Our review of symptomatic female AVPR2 heterozygotes includes 23 families with at least one affected female (including this study). There were 21 different causative mutations. Mutation types in females did not differ from those in males. Both severe XL-NDI and mild forms were reported in females. All six females with severe XL-NDI had complete loss-of-function (null) mutations. The remaining 17 female probands had milder XL-NDI caused by 14 missense variants and three null variants of the AVPR2 gene. X-inactivation was studied in nine of these females; all showed extreme or slight skewing. The review underlines that XL-NDI in female AVPR2 heterozygotes is always accompanied by skewed X-inactivation, emphasizing a need for X-inactivation studies in these females.
Asunto(s)
Acuaporina 2/genética , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Neurogénica/genética , Neurofisinas/genética , Precursores de Proteínas/genética , Receptores de Vasopresinas/genética , Vasopresinas/genética , Adolescente , Adulto , Diabetes Insípida Nefrogénica/epidemiología , Diabetes Insípida Nefrogénica/fisiopatología , Diabetes Insípida Neurogénica/epidemiología , Diabetes Insípida Neurogénica/fisiopatología , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatología , Femenino , Genes Ligados a X/genética , Humanos , Masculino , Mutación Missense/genética , Linaje , Secuenciación del Exoma , Inactivación del Cromosoma X/genética , Adulto JovenRESUMEN
In Germany, paternity testing can be ordered by a judge as well as by private persons. In the case of private counselling, the expert has the duty to inform the parties on all medical, legal and ethical aspects. Informed consent must be given by each individual included in an exploration of family relationships. Due to the rapid progress of DNA typing in even minute amounts after polymerase chain reaction amplification, genotypes of short tandem repeat systems can be elicited by extraction from single cells. Therefore, the number of unlawful investigations of paternal relationships is steadily increasing. Here the requirements for paternity testing laboratories and sanctions for unlawful exploration of a person's genotypes are discussed. A new Federal law should be drafted.