scholarly journals Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 206
Author(s):  
Sevcan Tug Bozdogan ◽  
Cem Mujde ◽  
Ibrahim Boga ◽  
Ozge Sonmezler ◽  
Abdullah Hanta ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Newborn Screening ◽  
Screening Program ◽  
Genetic Diagnosis ◽  
Hereditary Disease ◽  
Current Status ◽  
Treatment Center ◽  
Sweat Test ◽  
Molecular Testing

Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of CFTR mutations in Turkey. Methods: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017. Results: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (n = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation. Conclusion: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.

scholarly journals Clinical, Biochemical and Molecular Profile of Variant Galactosemia in Children Detected by National Newborn Screening: A Pilot Study

2017 ◽  
Vol 51 (3) ◽  
Author(s):  
Sylvia Capistrano-Estrada ◽  
Daffodil M. Canson ◽  
Catherine Lynn T. Silao
Keyword(s):  
Newborn Screening ◽  
Screening Program ◽  
Molecular Profile ◽  
Molecular Characteristics ◽  
Molecular Testing ◽  
Variant Form ◽  
Limited Information ◽  
Coding Region ◽  
Total Blood ◽  
Galt Activity

Objective. The observed irregularities in the biochemical profile and the limited information on long-term outcomes among patients with Duarte variant (D/G) galactosemia have led to patient management variability. This study examined the molecular characteristics of Filipino patients with presumed variant galactosemia for confirmation of diagnosis. It also aimed to describe the corresponding biochemical, clinical and neurodevelopmental profiles in order to gain a better understanding of the patients with normal galactose metabolites in spite of low to absent GALT activity detected by the local newborn screening program. Methods. Thirteen (13) patients who were presumed to have a variant form of galactosemia by national newborn screening between 2002 and 2010, and who previously underwent physical and neurodevelopmental assessment were included in the study. Repeat clinical, ophthalmologic and neurodevelopmental evaluations were done upon recruitment of participants. Direct sequence analysis of the coding region of the GALT gene was conducted to determine the patients’ genotypes. Results. None of the patients’ genotypes were consistent with Duarte variant (D/G) galactosemia. Their genotypes reflect the normal total blood galactose levels in patients, but were inconsistent with the absent or trace GALT activity. Conclusion. Molecular testing for the entire cohort of presumed “variant” galactosemia Filipino patients will provide better profiling of this condition. Re-evaluation and assessment of the current guidelines used by national newborn screening in classifying variant galactosemia are recommended.

Neonatal Screening for Cystic Fibrosis: Position Paper

PEDIATRICS ◽  
1983 ◽  
Vol 72 (5) ◽  
pp. 741-745 ◽  
Author(s):  
◽  
Lynn M. Taussig ◽  
Thomas F. Boat ◽  
Delbert Dayton ◽  
Norman Fost ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Newborn Screening ◽  
Neonatal Screening ◽  
Task Force ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Screening Tests ◽  
Current Status ◽  
Screening Methods ◽  
Asymptomatic Patients

Neonatal screening represents the search for a disorder in a general newborn population. The purpose of screening may be to improve the health of the affected infant, to provide counseling, or for research. Screening tests have been widely accepted for conditions such as phenylketonuria, hypothyroidism, and other metabolic conditions. Cystic fibrosis (CF) is the most common lethal genetic disorder among the white population (with a lower incidence among blacks), and thus there has been interest in screening newborns for CF1 However, proposals emanating from this interest have remained controversial.2-4 The recent development of a relatively simple test—the dried blood immuno-reactive trypsinogen (IRT) assay—has increased this interest.5-12 Besides considering technical reliability and validity of newborn screening methods, it is crucial that all other aspects of screening (including medical, ethical, psychosocial, and economic aspects) be rigorously examined before implementing mass screening.13-15 To address these issues the Cystic Fibrosis Foundation convened a Task Force on Neonatal Screening. Although the Task Force considered the current status of the IRT test, it focused on the generally accepted criteria for newborn screening, summarized in the Table,14 and the relationship of these criteria to the present state of knowledge related to CF. The issues identified by the Task Force, are summarized in this paper, and recommendations are presented at the conclusion. EFFECTIVENESS OF PRESYMPTOMATIC TREATMENT Evidence suggesting that the initiation of treatment before clinical manifestations of CF first appear improves prognosis has been controversial. Whereas some studies have yielded supportive data,16 others have not.4 There are no generally accepted treatment protocols for use in symptomatic or asymptomatic patients.

P016 First results from national newborn screening program for cystic fibrosis in the Republic of North Macedonia

2020 ◽  
Vol 19 ◽  
pp. S59
Author(s):  
S. Fustikj ◽  
V. Anastasovska ◽  
D. Plaseska Karanfilska ◽  
L. Spirevska ◽  
M. Pesevska ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Newborn Screening ◽  
Screening Program ◽  
Newborn Screening Program ◽  
First Results ◽  
The Republic

scholarly journals Newborn Screening for Cystic Fibrosis by Use of a Multiplex Immunoassay

2010 ◽  
Vol 56 (3) ◽  
pp. 445-450 ◽  
Author(s):  
Barbara A Lindau-Shepard ◽  
Kenneth A Pass
Keyword(s):  
Cystic Fibrosis ◽  
Newborn Screening ◽  
Screening Program ◽  
Pancreatic Disease ◽  
High Rate ◽  
Dna Testing ◽  
Second Tier ◽  
Sample Set ◽  
Positive Results ◽  
Immunoreactive Trypsinogen

Abstract Background: Since its beginnings, newborn screening for cystic fibrosis (CF) using an assay for immunoreactive trypsinogen (IRT) has been plagued by a high rate of false-positive results (screen positive, diagnosis negative), despite attempts to reduce this rate by use of altered cutoffs and second-tier DNA testing. IRT exists as 2 isoforms: IRT1 and IRT2, with IRT2 being more closely aligned with pancreatic disease, including CF. Assay standardization between programs is a continuing problem because the IRT assays currently in use variously recognize either 1 or both isoforms. Here we report the development of a multiplexed assay for both forms of IRT simultaneously. Methods: Using 2 different Luminex bead sets, we developed assays for each IRT isoform separately and then combined them. Using the sum of IRT1 and IRT2 values (IRT1+IRT2), we compared the results with a CF kit currently in use. Results: In a sample set consisting of 16 cases confirmed positive for CF, we established a cutoff at >97 μg/L total IRT. Seven of 8 carriers with 1 CF mutation screen-positive by the standard method were also screen-positive by IRT1+IRT2. Of 32 cases screen-positive by standard IRT, 11 were screen-negative by IRT1+IRT2. None of these 11 cases had CF mutations identified by the screening program. Conclusions: These data indicate that the multiplex method with specificity for 2 isoforms of IRT has performance comparable to that of a standard IRT method and the advantage of improved standardization by detection of the 2 isoforms.

Cystic fibrosis newborn screening: outcome of infants with normal sweat tests

2017 ◽  
Vol 103 (8) ◽  
pp. 753-756 ◽  
Author(s):  
Claire Edmondson ◽  
Christopher Grime ◽  
Ammani Prasad ◽  
Jacqui Cowlard ◽  
Chinedu E C Nwokoro ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Newborn Screening ◽  
Genome Sequencing ◽  
Dna Analysis ◽  
Gene Mutations ◽  
High Serum ◽  
Sweat Test ◽  
Sweat Chloride ◽  
South East England

Newborn babies positively screened for cystic fibrosis (CF) (high serum immunoreactive trypsin (IRT) with DNA analysis) are referred for a diagnostic sweat test, which may be normal (sweat chloride <30 mmol/L). Unless two gene mutations are identified during Newborn screening (NBS), the babies are discharged from follow-up. We wished to check that none had subsequently developed symptoms suggestive of CF. We retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in one of the four paediatric specialist CF centres in London, over the first 6 years of screening in South East England.Of 511 babies referred, 95 (19%) had a normal sweat test. Five (5%) had CF diagnosed genetically, two of them on extended genome sequencing after clinical suspicion. Eleven (12%) were designated as CF screen positive inconclusive diagnosis (CFSPID); one of the five CF children was originally designated as CFSPID. Seventy-nine (83%) were assumed to be false-positive cases and discharged; follow-up data were available for 51/79 (65%); 32/51 (63%) had no health issues, 19/51 (37%) had other significant non-CF pathology.These results are reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. The high non-CF morbidity in these children may relate to known causes of high IRT at birth. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is required.

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