Extending the clinical phenotype associated with biallelic <i>NTHL1</i> germline mutations

Fostira, Florentia; Kontopodis, Emmanouil; Apostolou, Paraskevi; Fragkaki, Maria; Androulakis, Nikolaos; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Saloustros, Emmanouil

doi:10.1111/cge.13444

Cited by 24 publications

(18 citation statements)

References 4 publications

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“…The first families described with NTHL1 mutations were of Dutch origin, all having the same truncating germline mutation (p.Gln90*) in a homozygous state (Weren et al, 2015). Since then, additional families of German, Spanish, British, and Greek descent with p.Gln90* mutations have been reported, in two cases in compound heterozygosity with another truncating NTHL1 mutation (c.709+1G > A and p.Gln287*, respectively) (Fostira et al, 2018;Belhadj et al, 2017;Chubb et al, 2016;Rivera et al, 2015;Weren et al, 2015). Three of these families have previously been described in detail (Belhadj et al, 2017;Rivera et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

et al. 2019

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Section: Introductionmentioning

confidence: 99%

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

et al. 2019

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“…It will be fair to assume that additional pathogenic variants with founder effect could be identified in other cancer‐predisposing genes, since the population of Crete is obviously characterized by a specific genetic architecture. Similarly, in a recent report relatively rare biallelic NTHL1 variants have been identified in two nonrelative males with adenomatous colorectal polyps, who originated from a village outside Heraklion, called Tylissos …”

Section: Discussionmentioning

confidence: 82%

“…Similarly, in a recent report relatively rare biallelic NTHL1 variants have been identified in two nonrelative males with adenomatous colorectal polyps, who originated from a village outside Heraklion, called Tylissos. 41 The evolution in the field of Genetics has already enabled the use of genetic information in everyday clinical practice. Moving forward to the future, the next step is to implement this valuable information toward cancer prevention by timely identification of asymptomatic carriers.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects

Apostolou

Fostira

Kouroussis

et al. 2020

Intl Journal of Cancer

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Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost-and timeefficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

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“…This observation is important when considering the natural history of colorectal polyposis associated with NTHL1 mutations and corroborates the current recommendation of colectomy when a considerable number of adenomas are identified. This case report is the second to describe a patient with a pathogenic homozygous NTHL1 variant affected with >100 colorectal polyps, both being males 10 . Previously, only four reported biallelic NTHL1 variant carriers have been described without malignant neoplasms, raising the number to six out of 32 patients without any malignant neoplasms when including the siblings.…”

Section: Other Family Membersmentioning

confidence: 82%

A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis

2019

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A new family with NTHL1-associated polyposis (NAP) is described, involving a 58-year-old male affected with >100 colorectal polyps and a 55-year-old female sibling with nine colorectal polyps. The female was also diagnosed with a thyroid adenoma at age 40. Significantly, no malignant neoplasms have been detected in this family, which is important to further delineate the clinical phenotype related to NAP. A review of previously reported obligate heterozygous carriers of NTHL1 variants showed two patients affected with neoplasms at <55 years of age, generating a study to outline the phenotypic spectrum in patients with heterozygous pathogenic NTHL1 variants relevant.

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Extending the clinical phenotype associated with biallelic NTHL1 germline mutations

Cited by 24 publications

References 4 publications

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects

A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis

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