Familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1: prevalence in a large healthcare population

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Familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1 : prevalence in a large healthcare population. / Dersham, Ridge; Gorvin, Caroline M; Metpally, Raghu; Krishnamurthy, Sarathbabu ; Smelser, Diane; Hannan, Fadil; Carey, David; Thakker, Rajesh; Breitwieser, Gerda E .

In: American Journal of Human Genetics, Vol. 106, No. 6, 07.05.2020, p. 734-747.

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Dersham, R, Gorvin, CM, Metpally, R, Krishnamurthy, S, Smelser, D, Hannan, F, Carey, D, Thakker, R & Breitwieser, GE 2020, 'Familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1: prevalence in a large healthcare population', American Journal of Human Genetics, vol. 106, no. 6, pp. 734-747. https://doi.org/10.1016/j.ajhg.2020.04.006

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Dersham, Ridge ; Gorvin, Caroline M ; Metpally, Raghu ; Krishnamurthy, Sarathbabu ; Smelser, Diane ; Hannan, Fadil ; Carey, David ; Thakker, Rajesh ; Breitwieser, Gerda E . / Familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1 : prevalence in a large healthcare population. In: American Journal of Human Genetics. 2020 ; Vol. 106, No. 6. pp. 734-747.

Bibtex

@article{709375c15dcf47249f104d256f305a1d,
title = "Familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1: prevalence in a large healthcare population",
abstract = "The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.",
keywords = "SKAT, Sequence Kernel Association Test, autosomal-dominant hypocalcemia type 1, calcium sensing receptor, disease associations, disease prevalence, familial hypocalciuric hypercalcemia type 1, genomics, serum calcium",
author = "Ridge Dersham and Gorvin, {Caroline M} and Raghu Metpally and Sarathbabu Krishnamurthy and Diane Smelser and Fadil Hannan and David Carey and Rajesh Thakker and Breitwieser, {Gerda E}",
year = "2020",
month = may,
day = "7",
doi = "10.1016/j.ajhg.2020.04.006",
language = "English",
volume = "106",
pages = "734--747",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Elsevier",
number = "6",

}

RIS

TY - JOUR

T1 - Familial hypocalciuric hypercalcemia type 1 and autosomal dominant hypocalcemia type 1

T2 - prevalence in a large healthcare population

AU - Dersham, Ridge

AU - Gorvin, Caroline M

AU - Metpally, Raghu

AU - Krishnamurthy, Sarathbabu

AU - Smelser, Diane

AU - Hannan, Fadil

AU - Carey, David

AU - Thakker, Rajesh

AU - Breitwieser, Gerda E

PY - 2020/5/7

Y1 - 2020/5/7

N2 - The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.

AB - The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.

KW - SKAT

KW - Sequence Kernel Association Test

KW - autosomal-dominant hypocalcemia type 1

KW - calcium sensing receptor

KW - disease associations

KW - disease prevalence

KW - familial hypocalciuric hypercalcemia type 1

KW - genomics

KW - serum calcium

UR - http://www.scopus.com/inward/record.url?scp=85084805287&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2020.04.006

DO - 10.1016/j.ajhg.2020.04.006

M3 - Article

C2 - 32386559

VL - 106

SP - 734

EP - 747

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -