Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia

Silva, Rita Santos; Carvalho, Berta; Pedro, Jorge; Castro-Correia, Cíntia; Carvalho, Davide; Carvalho, Filipa; Fontoura, Manuel

doi:10.20945/2359-3997000000437

Cited by 1 publication

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References 41 publications

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“…Correspondingly, symptomatic heterozygotes for genes related to neuromuscular disorders usually present with myalgias [ 5 , 6 ], mild muscular atrophy [ 11 ], and for hematological diseases with jaundice and mild symptoms of anemia [ 12 ] or familiar mild ptosis among the individuals with only one variant causative for congenital myasthenic syndrome (CMS), but where also cases of recessive CMS occurred [ 13 ]. In some cases, only some abnormalities in the laboratory tests may be detected [ 14 , 15 , 16 ]. This also suggests that it may be a disease phenotypic spectrum between heterozygous individuals and homozygous affected patients.…”

Section: Introductionmentioning

confidence: 99%

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Kalyta,

Stelmaszczyk,

Szczęśniak

et al. 2023

Genes

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Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur “later in life”. The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.

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