Targovnik Héctor M, Barh Debmalya, Papendieck Patricia, Adrover Ezequiela, Gallo Ariel M, Chiesa Ana, Marques da Silva Wanderson, Azevedo Vasco, Rivolta Carina M
Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Buenos Aires, Argentina.
Department of Genetics, Ecology & Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Endocrine. 2025 Mar;87(3):1150-1161. doi: 10.1007/s12020-024-04098-3. Epub 2024 Nov 28.
DICER1 syndrome is an autosomal-dominant disorder that results in malignant or benign tumors. A number of distinct pathogenic germline and somatic variants have been identified as causing multinodular goiter (MNG). The purpose of the present study was to identify and characterize the genetic cause underlying the familial form of MNG through a whole-exome sequencing (WES) analysis in an Argentine family with three affected siblings. Clinical, biochemical and molecular genetics as well as bioinformatics analysis were performed. A novel heterozygous variant in the DICER1 gene was identified in the proband patient by WES. The variant was a single guanine deletion at nucleotide position 2,042 (NM_177438.3:c.2042del) resulting in a frameshift at amino acid 681 with a putative premature stop codon [NP_803187.1:p.Gly681ValfsTer4]. Family segregation analysis showed that his affected sister and his affected brother also were heterozygous for same variant, whereas the father was a healthy heterozygous carrier of the variant and the healthy mother harbor only wild-type alleles in the DICER1 gene. We have also observed that the frameshift variant does not interfere with the pre-mRNA splicing of the exon 13. In addition, two clinically relevant heterozygous variants, not associated with thyroid disease, were also identified in index sibling using the Franklin platform, a frameshift [NP_000234.1:p.Thr55AsnfsTer49] in the MEFV gene (familial mediterranean fever) and a missense [NP_004530.1:p.Ala422Thr] in the NARS1 gene (neurodevelopmental delay and ataxia). In conclusion, in the present study we have identified a novel frameshift variant corresponding to NP_803187.1:p.Gly681ValfsTer4 in the DUF 283 domain of DICER1. The results were in accordance with previous observations confirming the genetic heterogeneity of DICER1 syndrome. Moreover, the identification of this variant in the unaffected father substantiates the hypothesis of incomplete/reduced penetrance.
DICER1综合征是一种常染色体显性疾病，可导致恶性或良性肿瘤。一些不同的致病种系和体细胞变异已被确定为导致多结节性甲状腺肿（MNG）的原因。本研究的目的是通过对一个有三名患病兄弟姐妹的阿根廷家庭进行全外显子组测序（WES）分析，来识别和表征家族性MNG的潜在遗传病因。进行了临床、生化、分子遗传学以及生物信息学分析。通过WES在先证者患者中鉴定出DICER1基因中的一种新型杂合变异。该变异是核苷酸位置2042处的单个鸟嘌呤缺失（NM_177438.3:c.2042del），导致第681位氨基酸移码，并带有一个推定的过早终止密码子[NP_803187.1:p.Gly681ValfsTer4]。家系分离分析表明，他患病的姐姐和哥哥也为该变异的杂合子，而父亲是该变异的健康杂合携带者，健康的母亲在DICER1基因中仅携带野生型等位基因。我们还观察到，移码变异并不干扰外显子13的前体mRNA剪接。此外，使用富兰克林平台在先证者同胞中还鉴定出两个与甲状腺疾病无关的临床相关杂合变异，一个是MEFV基因中的移码变异[NP_000234.1:p.Thr55AsnfsTer49]（家族性地中海热），另一个是NARS1基因中的错义变异[NP_004530.1:p.Ala422Thr]（神经发育迟缓与共济失调）。总之，在本研究中，我们在DICER1的DUF 283结构域中鉴定出一种与NP_803187.1:p.Gly681ValfsTer4相对应的新型移码变异。结果与先前的观察结果一致，证实了DICER1综合征的遗传异质性。此外，在未患病的父亲中鉴定出该变异证实了不完全/降低外显率的假说。
