Iris Publishers- Open access Journal of Gynecology & Women's Health | Carrier Rate of Citrullinemia, Type I in Individual Ethnic Groups Using an Expanded Carrier Test

 

Authored by Jonah Bardos

Purpose: To identify population-specific carrier frequencies for Citrullinemia Type 1. Better knowledge of population specific carrier frequencies improves carrier testing and genetic counseling; however, prior reports have not captured data in specific ethnic groups. Identifying a fetus at risk for CTLN1 could allow prenatal planning by arranging for appropriate post-partum care to mitigate or prevent long lasting neurological damage with prompt use of metabolic therapy.
Methods: Retrospective review of 11,132 individuals who underwent expanded carrier testing utilizing a genotyping panel. The CTLN1 variants included were the common 1168G>A variant, and the rarer 421-2A>G/910C>T variant. Adjusting for the genotyping panel’s detection rate we calculated the carrier frequency for specific ethnic groups.
Results: Pan-ethnic carrier frequency of 1:383 (10*2.9/11,132), corresponding to a population prevalence of 1: 575,000. Adjusted carrier rates are: 1/124 in the Ashkenazi Jewish group; 1/392 in the Hispanic group;1/422 in the Caucasian/White group.
Conclusion: As expanded carrier testing utilization increases, it is important to continue to reassess carrier and disease frequencies of rare conditions with large ethnically diverse cohorts. This is the first report, to our knowledge, to document CTLN1 carrier rate in individual ethnic groups. This knowledge can guide preconception and prenatal counseling enabling patients and providers to identify resources and neonatal management options.
Precis: CTLN1 carrier rates vary amongst different ethnic groups.

Introduction

Citrullinemia type I (CTLN1) is an autosomal recessive urea cycle disorder characterized by an arginosuccinate synthetase (ASS1 EC 6.3.4.5) enzyme deficiency. ASS1 is a urea cycle enzyme predominantly expressed in periportal hepatocytes which catalyzes the formation of arginosuccinate from citrulline and aspartate [1-3]. Type 1, or classical citrullinemia (CTLN1: OMIM#215700) is caused by pathogenic variants in the ASS gene, most commonly a missense in exon 15 of 1168G>A .2 The presence of this variant decreases ASS1 enzyme function, leading to the accumulation of citrulline and hyperammonemia [4,5]. Effects of this condition can be devastating, with long-term neurological deficits including spasticity, seizures, loss of consciousness, and death. 6 Identifying a fetus at risk for CTLN1 could allow prenatal planning by arranging for appropriate post-partum care to mitigate or prevent long lasting neurological damage with prompt use of metabolic therapy [7].

The prevalence of CTLN1 is estimated at 1 in 57,000 live births.7 Previously published papers out of the United States reported a wide-ranging prevalence between 1:36,000 to 1: 250,000 or a carrier frequency ranging from 1:95 to 1:250 [8-10]. Knowledge of population-specific carrier frequencies improves carrier testing and genetic counseling; however, prior reports have not captured data in specific ethnic groups.

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