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A female with X-linked Nephrogenic diabetes insipidus in a family with inherited central diabetes Insipidus: Case report and review of the literature.
Am J Med Genet A. 2020 05; 182(5):1032-1040.AJ

Abstract

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.

Authors+Show Affiliations

Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.Pediatric Nephrology Unit of the Children's Hospital, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32073219

Citation

Ding, Can, et al. "A Female With X-linked Nephrogenic Diabetes Insipidus in a Family With Inherited Central Diabetes Insipidus: Case Report and Review of the Literature." American Journal of Medical Genetics. Part A, vol. 182, no. 5, 2020, pp. 1032-1040.
Ding C, Beetz R, Rittner G, et al. A female with X-linked Nephrogenic diabetes insipidus in a family with inherited central diabetes Insipidus: Case report and review of the literature. Am J Med Genet A. 2020;182(5):1032-1040.
Ding, C., Beetz, R., Rittner, G., & Bartsch, O. (2020). A female with X-linked Nephrogenic diabetes insipidus in a family with inherited central diabetes Insipidus: Case report and review of the literature. American Journal of Medical Genetics. Part A, 182(5), 1032-1040. https://doi.org/10.1002/ajmg.a.61516
Ding C, et al. A Female With X-linked Nephrogenic Diabetes Insipidus in a Family With Inherited Central Diabetes Insipidus: Case Report and Review of the Literature. Am J Med Genet A. 2020;182(5):1032-1040. PubMed PMID: 32073219.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A female with X-linked Nephrogenic diabetes insipidus in a family with inherited central diabetes Insipidus: Case report and review of the literature. AU - Ding,Can, AU - Beetz,Rolf, AU - Rittner,Gabriele, AU - Bartsch,Oliver, Y1 - 2020/02/19/ PY - 2019/11/11/received PY - 2020/01/16/revised PY - 2020/01/28/accepted PY - 2020/2/20/pubmed PY - 2021/1/13/medline PY - 2020/2/20/entrez KW - AVP KW - AVPR2 KW - affected female KW - central (neurohypophyseal) diabetes insipidus KW - gender medicine KW - nephrogenic (renal) diabetes insipidus SP - 1032 EP - 1040 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 182 IS - 5 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/32073219/A_female_with_X_linked_Nephrogenic_diabetes_insipidus_in_a_family_with_inherited_central_diabetes_Insipidus:_Case_report_and_review_of_the_literature_ L2 - https://doi.org/10.1002/ajmg.a.61516 DB - PRIME DP - Unbound Medicine ER -