A frequent oligogenic involvement in congenital hypothyroidism

Abstract

Congenital hypothyroidism (CH), the most frequent form of preventable mental retardation, is predicted to have a relevant genetic origin. However, CH is frequently reported to be sporadic and candidate gene variations were found in <10% of the investigated patients. Here, we characterize the involvement of 11 candidate genes through a systematic Next Generation Sequencing (NGS) analysis. The NGS was performed in 177 unrelated CH patients (94 gland-in-situ; 83 dysgenesis) and in 3,538 control subjects. Non-synonymous or splicing rare variants (MAF < 0.01) were accepted, and their functional impact was predicted by a comprehensive bioinformatic approach and co-segregation studies. The frequency of variations in cases and controls was extended to 18 CH-unrelated genes. At least one rare variant was accepted in 103/177 patients. Monogenic recessive forms of the disease were found in five cases, but oligogenic involvement was detected in 39 patients. The 167 variations were found to affect all genes independently of the CH phenotype. These findings were replicated in an independent cohort of additional 145 CH cases. When compared to 3,538 controls, the CH population was significantly enriched with disrupting variants in the candidate genes (P = 5.5 × 10-7), but not with rare variations in CH-unrelated genes. Co-segregation studies of the hypothyroid phenotype with multiple gene variants in several pedigrees confirmed the potential oligogenic origin of CH. The systematic NGS approach reveals the frequent combination of rare variations in morphogenetic or functional candidate genes in CH patients independently of phenotype. The oligogenic origin represents a suitable explanation for the frequent sporadic CH occurrence.

Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

“…Thus, those examined as athyreosis could not be excluded for the likelihood of ectopy. Similarly, other studies have found variants associated with dH in patients with athyreosis (30,32). in addition, 2 individual variants in genes associated with pituitary development or central cH (PROP1 and TRHR) respectively were found in 1 cH patient with GiS and 1 patient with Td, and both variants co-occurred with genetic variants associated with DH.…”

Molecular defects in thyroid dysgenesis

“…Because of the wide phenotypic variation of either thyroid hypoplasia or ectopy, it is conceivable to think that these abnormalities could be determined by variation of quantitative traits, that is, thyroid cells growth and migration, respectively, as a result of polygenic effects. Targeted NGS studies in TD patients' cohorts highlighted that heritable mutations accounts for at least 50% of patients . Moreover, according to what was revealed using mouse models, a significant proportion of patients have multiple gene variations in more than one thyroid specific gene.…”

“…Targeted NGS studies in TD patients' cohorts highlighted that heritable mutations accounts for at least 50% of patients. 86 Moreover, according to what was revealed using mouse models, 46 a significant proportion of patients have multiple gene variations in more than one thyroid specific gene. Importantly, some TD candidate gene variations highlighted so far can be assessed also in the general population with a significantly lower prevalence, 15 indicating that the of pathogenesis of TD can be due to the sum of multiple rare alleles that act in concert to generate the pathological phenotype.…”

TUBB 1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

“…These hypotheses are already documented in the literature for TD (Deladoëy et al , ; Magne et al , ). Finally, the genetics of TD remains complex with mutations in more than nine known genes and both classical and complex modes of inheritance, such as a suggested oligogenic model by Persani et al (de Filippis et al , ). The same genetic pattern of inheritance is also observed in other endocrine‐related disorders such as congenital hypogonadotropic hypogonadism (Boehm et al , ) or in the more complicated genetic model of Bardet–Biedl syndrome (Muller et al , ).…”