Abstract
Several metabolic disorders follow an autosomal recessive inheritance pattern. Epidemiological information on these disorders is usually limited in developing countries. Our objective is to assess carrier frequencies of rare autosomal recessive metabolic diseases in a cohort of Brazilian patients that underwent molecular investigation with exome sequencing and estimate the overall frequency of these diseases using the Hardy-Weinberg equation. We reviewed the molecular findings of 320 symptomatic patients who had carrier status for recessive diseases actively searched. A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic (P/LP) variant for rare metabolic disorders. Most of these variants are harbored by genes associated with multisystemic involvement. We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000. This study shows the potential research utility of exome sequencing to determine carrier status for rare metabolic diseases, which may be a possible strategy to evaluate the clinical and social burden of these conditions at the population level and guide the optimization of health policies and newborn screening programs.
Highlights
Inborn metabolic diseases are a complex group of disorders of genetic background that affect biosynthesis or breakdown of substances within specific pathways, recognizable by specific biochemical tests [1]
A total of 205 rare variants were reported in 138 different genes associated with metabolic diseases from 156 patients, which represents that almost half (48.8%) of the patients were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders
We estimated the overall frequency for rare recessive metabolic diseases to be 10.96/10,000 people, while the frequency of metabolic diseases potentially identified by newborn screening was estimated to be 2.93/10,000
Summary
Inborn metabolic diseases (in this article referred to as “metabolic diseases”) are a complex group of disorders of genetic background that affect biosynthesis or breakdown of substances within specific pathways, recognizable by specific biochemical tests [1] The majority of these disorders present monogenic etiology, autosomal recessive inheritance and multisystemic involvement. A rapid diagnosis is key for favorable long-term prognosis for several of these disorders because 1) some affected individuals can die during an acute metabolic crisis and 2) several of these disorders are treatable by special diets, vitamins, cleansing drugs or other newly-developed treatments [2] For this reason, the majority of nations have created universal newborn screening for some treatable metabolic disorders that are potentially recognized through this early approach. The Newborn Screening ACT Sheets and Algorithms (ACMG ACT Sheets) [3] are a good resource for mapping metabolic diseases that may be identified through newborn screening
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