Loss-of-Function Variants in as Modifying Factors in Beta-Thalassemia.

It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association in carriers of Loss-of-Function variants with a beta-thalassemia-like phenotype including the characteristic elevated levels of HbA. That acts as modifier in beta-thalassemia carriers became evident from three reported cases in whom combined heterozygosity of and gene variants was observed to resemble a mild beta-thalassemia intermedia phenotype.

The hemoglobinopathies, molecular disease mechanisms and diagnostics.

Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries.

Calibration by commutable control materials is able to reduce inter-method differences of current high-performance methods for HbA.

Background: Most of the current methods used for the determination of HbA seem not well aligned. A comparison among the best performing techniques and the commutability of some control materials currently available and under development has been evaluated.

Methods: Forty blood samples were analyzed in duplicate over two separate days by different HPLC and capillary electrophoresis systems.

Melanocortin 1 receptor (MC1R) variants in high melanoma risk patients are associated with specific dermoscopic ABCD features.

Individuals with two red hair colour (RHC)-MC1R genetic variants have light skin and blond/reddish hair and, in comparison with those without such alleles, are at an increased risk of developing melanoma. Our study investigated the association of RHC variants and the Total Dermo-scopy Score (TDS), and the items that make up the TDS, in those with atypical naevi and melanomas from high risk melanoma patients. Eight hundred and seventy-six atypical naevi and 21 melanomas were scored according to the TDS system and MC1R polymorphisms were determined.

Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.

Purpose: We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for the same CDKN2A mutation.

Experimental Design: We studied family members of 22 families positive for the p16-Leiden founder mutation who had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person and their relatives.

Genetic testing in familial melanoma: uptake and implications.

Objective: We report on the uptake and psychological impact of p16-Leiden genetic testing to contribute to a greater understanding of counseling melanoma families.

Methods: Within a defined research setting, genetic counseling and testing were offered to members of p16-Leiden-positive melanoma pedigrees, at risk of carrying a gene defect associated with an increased risk of melanoma and pancreatic cancer.

Results: One hundred and eighty-four individuals sought counseling, of which 141 (77%) opted for genetic testing.

A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL).

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing.

From sporadic atypical nevi to familial melanoma: risk analysis for melanoma in sporadic atypical nevus patients.

Background: Atypical nevi (AN), present in either a familial or a sporadic setting, are strong indicators of increased melanoma risk.

Objective: To estimate the extent of this risk and the extent of reclassification of sporadic to familial cases during follow-up.

Methods: We studied 167 sporadic patients with AN (>or=5).

A mutation hotspot at the p14ARF splice site.

Germline mutations of CDKN2A that affect the p16INK4a transcript have been identified in numerous melanoma pedigrees worldwide. In the UK, over 50% of pedigrees with three or more cases of melanoma have been found to carry mutations of CDKN2A. Mutations that affect p14ARF exon 1beta exclusively are very rare.