Anaemia-based screening for resistance to thyroid hormone alpha in children.

BACKGROUND: The hypothyroid phenotype associated with resistance to thyroid hormone alpha (RTH-α) is associated with a diverse clinical picture. On the other hand, thyroid-stimulating hormone (TSH) levels are normal. Free triiodothyronine (fT3) and free thyroxine (fT4) levels can also be normal; however, normo- or macrocytic anaemia is usually present in reported cases. Diagnosis is challenging and there is limited data regarding screening methods. OBJECTIVE: The study aimed to assess the efficiency of a screening strategy for RTH-α. SUBJECTS AND METHODS: Out of a total of 6540 children evaluated at the outpatient clinics of paediatric neurology over 2 years and who underwent complete blood count and thyroid function tests, 432 were found to have anaemia. Within this group, we identified 42 children without an underlying specific neurological aetiology who exhibited normo- or macrocytic anaemia, normal TSH levels, fT3 levels in the upper half of the normal range or high, and fT4 levels in the lower half of the normal range or low. We excluded one patient who had already been diagnosed with RTH-α and nine patients could not be reached. Subsequently, clinical evaluation, biochemical assessment, and THRA sequencing analysis were conducted on 32 children. The findings were compared with those of the known RTH-α patients in our unit. RESULTS: The median age of the patients was 5.7 (5.1-7.4) years, and 22 of them were males (69%). The main reasons for assessment in paediatric neurology clinics were autism spectrum disorder (n = 12, 38%), epilepsy (n = 11, 34%), and delay in developmental stages (n = 8, 25%). Constipation was present in five of the cases (16%), while the closure of the anterior fontanelle and tooth eruption were delayed in two cases (6%) and one case (3%), respectively. The median length/height and weight standard deviation (SD) scores were 0.3 [(-0.8)-(1.1)] and -0.1 [(-0.8)-(0.3)], respectively. The median fT3, fT4, and TSH levels were 4.6 (4.2-5.0) pg/mL, 0.9 (0.8-1.0) ng/dL, and 2.2 (1.8-3.1) uIU/mL, respectively. Thirteen of the patients (41%) had high fT3 levels, while none of them had low fT4 levels. The normo- or macrocytic anaemia rate was 47% (normocytic/macrocytic, n = 8/7) at the time of reassessment. Serum creatine kinase (CK) was elevated in five patients (16%; one had anaemia). None of the subjects had a pathological variant in THRA. Known RTH-α patients had significantly lower median height SD score, higher rates of delayed tooth eruption and closure of the anterior fontanelle, lower haemoglobin levels, and higher mean corpuscular volume (MCV) and CK levels as compared to those found without RTH-α. CONCLUSIONS: This approach found one known patient with RTH-α but did not reveal any new cases. Notably, normo- or macrocytic anaemia did not persist in nearly half of the screened patients. A screening strategy that takes clinical findings and prominent laboratory features suggestive of RTH-α into account could lower unnecessary genetic analysis of THRA in patients presenting with neurological problems.

Experiences in the molecular genetic and histopathological evaluation of calpainopathies.

Calpainopathy is mainly characterized by symmetric and progressive weakness of proximal muscles. Several reports showed that the most common LGMD subtype is LGMDR1 or calpainopathy, which had previously been defined as LGMD2A. Until now, more than 500 likely pathogenic/pathogenic variants in the CAPN3 gene have been reported. However, a clear genotype-phenotype association had not yet been established and this causes major difficulties in predicting the prognosis in asymptomatic patients and in providing genetic counseling for prenatal diagnosis. In this report, we aimed to add new data to the literature by evaluating 37 patients with likely pathogenic/pathogenic variants for the detected variants' nature, patients' phenotypes, and histopathological features. As a result, the general clinical presentation of the 23 different variants was presented, the high frequency of NM_000070.3:c.550delA mutation in Exon 4 was discussed, and some novel genotype-phenotype associations were suggested. We have underlined that calpainopathy can be misdiagnosed with inflammatory myopathies histopathologically. We have also emphasized that, in young or adult patients with mild to moderate proximal muscle weakness and elevated CK levels, calpainopathy should be the first suspected diagnosis.

Neonatal classic galactosemia-diagnosis, clinical profile and molecular characteristics in unscreened Turkish population.

BACKGROUND: Classic galactosemia (CG) is a rare hereditary disease that can cause serious morbidity and death if it is not diagnosed and treated in early periods of life. Clinical findings usually occur in the neonatal period after the neonate is fed with milk that contains galactose. Most patients are presented with jaundice, hepatomegaly, hypoglycemia and cataracts. OBJECTIVE: We aimed to document the clinical, molecular characteristics, regional estimated incidence and time of diagnosis in newborn with CG. MATERIALS AND METHOD: The data of 63 newborn with CG who were diagnosed and followed up between January 2011 and January 2018 were analyzed retrospectively. RESULTS: During the study period, 63 (33 boys and 30 girls) newborns were diagnosed with CG. The median gestational age was 39 weeks (33-42). Major presenting symptoms were jaundice 90.5% and cataract 41.2%. The mean age at first symptom was 12 ± 7.4 days while the mean age at diagnosis was 18.9 ± 10.6 days. Nearly half of the patients (55.5%) were diagnosed later than the postnatal 15th day. Genetic analysis was performed on 56 patients and homozygous Q188R mutation was found in 92.8%. There were signs of sepsis in 33.3% of the cases. Six patients died due to sepsis. There was consanguinity in 84.1% of the parents and regional estimated incidence was calculated as 1 in 6103 live births. CONCLUSION: Q188R mutation was found in 92.8% of our cases. The regional estimated incidence was found as 1 in 6103 live births. Our study strongly supports that galactosemia should be included in the national newborn screening program.

JAK2V617F, CALR and MPL515L/K mutations and plateletcrit in essential thrombocythemia: A single centre's experience.

AIMS: JAK2V617F (JAK2), calreticulin (CALR) and MPL515L/K (MPL) mutations are important in essential thrombocythemia (ET) and may be associated with various clinical consequences of the disease. This study aimed to compare the clinical and haematological parameters of ET patients regarding the mentioned mutations and the role of plateletcrit (PCT). METHODS: Seventy patients who were diagnosed with ET between 2005 and 2017 in a single centre were included in this descriptive study. The initial symptoms and clinical findings were retrieved from the electronic database. JAK2 gene V617F mutations, MPL gene exon 10 mutations and CALR gene exon 9 DNA sequence analyses were performed. Forty-one healthy volunteers were included to perform ROC curve analysis for interpreting PCT value. RESULTS: The distributions of patients according to the mutations were as follows: Thirty-seven (52.9%) patients were JAK2-positive, 15 (21.4%) were CALR-positive, 2 (2.8%) patients were positive for both CALR and JAK2, and 1 (1.4%) was only MPL-positive. Fifteen (21.4%) patients were triple-negative. The ET patients with JAK2 mutation showed a higher level of haemoglobin at the time of diagnosis. The ET patients with CALR mutation presented with higher platelet and LDH levels (P = .002 and P = .001, respectively). The PCT level was higher in the CALR-positive group when compared to the others (P = .026). A sensitivity value of 97.6% and specificity value of 98.6% were determined regarding PCT% at a cut-off value of 0.37 in ET patients. In CALR-positive patients, the sensitivity and specificity values were 100% for the PCT at a cut-off value of 0.42%. CONCLUSION: We determined that the platelet count and blood LDH level was high in the ET patient group with CALR mutation. Besides, we found that the blood haemoglobin level was higher in the ET patient group with JAK2 mutation. Additionally, the PCT level was higher in the CALR group when compared to the other patient groups.

Impact of next-generation sequencing panels in the evaluation of limb-girdle muscular dystrophies.

INTRODUCTION: Limb-girdle muscular dystrophy (LGMD) is the fourth most common muscular dystrophy, with progressive proximal muscle weakness. However, a large number of neuromuscular conditions are similarly presented. Because of this, the use of high-throughput methods such as next-generation sequencing (NGS) is important in the evaluation of LGMD. METHODS: In this report, we applied a custom target capture-based NGS panel covering 31 LGMD-associated genes (MYOT, LMNA, CAV3, DES, DNAJB6, FLNC, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FRKP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT1, DAG1, PLEC, GAA, GMPPB, HNRNPDL, TNPO3, LIMS2, POMK, TRAPPC11, ISPD) in 74 patients suspected of LGMD. RESULTS: In 25 (33.8%) out of 74 patients analyzed, one or more pathogenic/likely pathogenic variants in 13 different genes were detected. Six of the patients had the variants that were not found in databases and literature; thus, they were interpreted as novel pathogenic variants. DISCUSSION: The diagnosis rate achieved (33.8%) is consistent with previous literature reports and underlines the efficiency and importance of NGS technology in the molecular genetic evaluation of LGMD.

Unexpected Coexistence of a Derivative t(21;21) and Complementary Mosaic r(21) in a Female with Multiple Miscarriages.

The case presented here describes a female patient with recurrent miscarriages and a normal microarray analysis result. However, the coexistence of a robertsonian (21;21) translocation and complementary mosaic ring chromosome 21 was detected by karyotyping and FISH analysis. Partial trisomy 21 was found with QF-PCR and microarray analysis in one of the fetuses. The aim of this report was to emphasize the diagnostic importance of conventional cytogenetics.

Molecular genetic evaluation of NLRP3, MVK and TNFRSF1A associated periodic fever syndromes.

Periodic fever syndromes (PFSs) are a family of clinical disorders, which are characterized by recurrent episodes of fever in the absence of microbial, autoimmune or malign conditions. Most common types of PFSs are associated with four genes: MEFV, MVK, TNFRSF1A and NLRP3. This paper aims to add new data to the genotype-phenotype association of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. A total number of 211 patients were evaluated. Two different approaches were used for the molecular genetic evaluation of MVK-, TNFRSF-1A- and NLRP3-associated PFSs. For the first 147 patients, Sanger sequence analysis of selected exons of MVK, TNFRSF1A and NLRP3 genes was done. For subsequent 64 patients, targeted NGS panel analysis, covering all exons of MVK, TNFRSF1A and NLRP3 genes, was used. A total number of 48 variants were detected. The "variant detection rate in index patients" was higher in the NGS group than Sanger sequencing group (19% vs. 15,1%). For the variant positive patients, a detailed genotype-phenotype table was built. In PFSs, lack of correlation exists between genotype and phenotype in the general population and even within the families. In some cases, mutations behave differently and yield unexpected phenotypes. In this study, we discussed the clinical effects of eight different variants we have detected in the MVK, TNFRSF1A and NLRP3 genes. Four of them were previously identified in patients with PFS. The remaining four were not reported in patients with PFS. Thus, we had to interpret their clinical effects by analysing their frequencies and in silico analysis predictions. We suggest that new studies are needed to evaluate the effects of these variants more clearly. To be able to demonstrate a clearer genotype-phenotype relationship, all PFS-related genes should be analysed together and the possibility of polygenic inheritance should be considered.

Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum.

Ring chromosome 13 is a rare genetic condition with an incidence of 1/58,000 in live births. Major clinical features of patients with ring chromosome 13 include growth and developmental retardation, microcephaly, facial dysmorphism, ambiguous genitalia, anal atresia, eye malformations, retinoblastoma, and hand, foot, and toe abnormalities. The severity of the phenotype depends on the amount of genetic material lost during ring chromosome formation. Here, we report 2 cases with ring chromosome 13 at either end of the phenotypic spectrum.

Mutations in the human UBR1 gene and the associated phenotypic spectrum.

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

Investigation of EGFR and ALK mutation frequency and treatment results in advanced non-small cell lung cancer.

Aim: Lung cancer has opened a new era in cancer treatment by elucidating the tumor's molecular structure and identifying the targetable mutations. Identifying the targeted mutations in lung cancer constitutes one of the main steps of treatment planning. The frequency of EGFR (epidermal growth factor receptor gene) and ALK (anaplastic lymphoma kinase gene) mutations in non-small cell lung cancer (NSCLC) also varies in populations depending on ethnicity, gender, smoking, and histopathological subtype. In general, limited data are available regarding the frequency and regional distribution of these mutations in the Turkish population. Our study aimed to determine the frequency of EGFR and ALK mutations in patients with advanced-stage NSCLC and compare the clinical characteristics, treatment, and survival results of cases with mutations with the group without mutations. Materials and Methods: In our study, 593 patients with advanced-stage NSCLC diagnosis and mutational analyses were evaluated retrospectively. Demographic characteristics, tumor stages (tumor, node, metastasis, TNM), EGFR and ALK analysis results, treatments applied, and survival of the cases were recorded. EGFR analysis, exon 18, 19, 20, and 21 mutations were studied with real-time PCR (RT-PCR) Rotor-Gene system from patients' samples. For ALK analysis, the ALK Break Apart kit (Zytovision GmbH; Germany) was used with the fluorescent in situ hybridization (FISH) method. Results: In our study, EGFR mutation was detected in 63 patients (10.6%) and ALK mutation in 19 patients (3.2%) out of 593 patients. EGFR mutation was observed more frequently in women and non-smokers (P = 0.001, P = 0.003). No correlation was found between the presence of EGFR mutation and metastases regions and recurrence (P > 0.05). ALK mutation was observed more frequently in non-smokers and females (P = 0.001, P = 0.003). Patients with ALK mutations were younger than other groups (P = 0.003). There was also no significant relationship between ALK mutation and metastates regions and recurrence after treatment (P > 0.05). Patients with EGFR or ALK mutations had a longer life span than other cases (P = 0.474). Those who had ALK mutations and received targeted therapy had a longer average life expectancy (P < 0.05). No difference was observed in those who had EGFR mutations and received targeted treatment in terms of survival (P > 0.05). Conclusion: In our study, conducted in the Aegean region of Turkey, the positivity rates of EGFR and ALK mutations were found to be at similar rates with the Caucasian race across the world. EGFR mutation was more common in women, non-smokers, and patients with adenocarcinoma histology. ALK mutation was also detected more frequently in younger patients, women, and non-smokers. Patients with EGFR and ALK mutations had a longer life expectancy than those without the mutation. It was observed that testing patients diagnosed with advanced-stage NSCLC for genetic mutations of the tumor in the first step of the treatment and initiating treatment in patients with mutations provided a significant survival advantage.

Atypical Presentation and Course of ACTH-independent Cushing's Syndrome in Two Families.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare genetic disease mainly associated with Carney complex (CNC), which is caused by germline mutations of the regulatory subunit type 1A (RIα) of the cAMP-dependent protein kinase (PRKAR1A) gene. We report three cases suffering from CNC with unique features in diagnosis and follow-up. All cases had obesity and a cushingoid appearance and exhibited laboratory characteristics of hypercortisolism. However biochemical and radiological examinations initially suggested Cushing's disease in one case . All of the cases were treated surgically; two of them underwent bilateral adrenalectomy at once, one of them had unilateral adrenalectomy at first but required contralateral adrenalectomy after nine months. Contrary to what is usually known regarding PPNAD, the adrenal glands of two cases (case 2 and 3) had a macronodular morphology. Genetic analyses revealed pathogenic variants in PRKAR1A (case 1: c.440+5 G>A, not reported in the literature; cases 2 and 3: c.349G>T, p.V117F). One case developed Hodgkin lymphoma five year after adrenalectomy, this association was not previously reported with CNC. The findings of these families provide important information for a better understanding of the genetic pathogenesis, diagnosis, and clinical management of CNC. Hodgkin lymphoma may be a component of CNC.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1): a rare cause of hypotonia, diaphragmatic weakness, and respiratory failure in infants.

BACKGROUND: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive disorder caused by mutations in the immunoglobulin µ-binding protein-2 (IGHMBP2) gene on chromosome 11q13.2-q13.4. The initial symptoms of patients with SMARD1 are respiratory distress and distal muscle weakness manifesting in the infantile period due to progressive degeneration of α-motor neurons. Preterm birth, intrauterine growth retardation, feet deformities, sensory and autonomic neuropathy are other main features. CASE: Herein, we report the characteristics of a 6-year-old Turkish girl with a diagnosis of SMARD1 confirmed by homozygous c.1738G > A (p.Val580Ile) missense IGHMBP2 variant. She had unusual features such as vocal cord paralysis, nystagmus, and lack of congenital foot deformities besides typical findings including hypotonia, respiratory distress, and diaphragmatic weakness in the early infantile period. Epileptic seizures, cognitive impairment, and brain magnetic resonance imaging (MRI) abnormalities were other, unexpected, features which developed during the course of the disorder possibly due to several hypoxic episodes. CONCLUSIONS: SMARD1 should be kept in mind in hypotonic infants with diaphragmatic weakness and respiratory failure during the early infantile period, even in the presence of unexpected findings including vocal cord paralysis, nystagmus, epileptic seizures, and brain MRI abnormalities.

ALK, ROS1 and EGFR status of lung cancers in the Aegean Region of Turkey.

Background/Aims: As targeted therapies are promising in the treatment of lung cancer (LC), it is important to identify the genetic variations in tumors. The present research aimed to determine the regional prevalence of alterations in ALK, ROS1, and EGFR genes. Materials and. Methods: ALK rearrangement in 1152, ROS1 rearrangement in 390, and EGFR mutations in 1054 cases with LC were evaluated. Results: Alteration rates of ALK, ROS1, and epidermal growth factor receptor (EGFR) genes were 3.5%, 0.4%, and 11.2% in the samples, respectively. ALK rearrangements were mainly detected in young patients (P < 0.01) and in females (P < 0.01). Females were also more often inflicted by EGFR variations, especially from the exon 19 deletion. Exon 21 L858R mutations were more frequently found in men. However, any statistical significance between EGFR alterations and gender or age was not discovered. Conclusion: In this study, molecular changes were less frequent than expected. We thought that this low rate confirmed the aphorism of "smokes like a Turk, " which could be because almost all patients were active or passive smokers.

Childhood-onset mild diabetes caused by a homozygous novel variant in the glucokinase gene.

PURPOSE: Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause MODY 2, which is characterized by asymptomatic fasting hyperglycemia and does not require insulin treatment. Conversely, homozygous loss-of-function mutations in the same gene give rise to permanent neonatal diabetes mellitus (DM) that appears in the first 6-9 months of life and necessitates lifelong insulin treatment. We aimed to present the genotypic and phenotypic features of a 13-year-old patient diagnosed with DM at the age of 3 years due to a homozygous variant in the GCK gene. METHODS: The patient's clinical and laboratory findings at follow-up were not consistent with the initial diagnosis of type 1 DM; thus, next-generation sequencing of MODY genes (GCK, HNF1A, HNF1B, and HNF4A genes) was performed to identify monogenic causes of DM. RESULTS: A novel homozygous variant c.1222 G > T in the GCK gene was revealed. In silico analysis identified it as a pathogenic variant. His mother, father, and brother had the same heterozygous variant in the GCK gene and were diagnosed with MODY 2 (mild fasting hyperglycemia and elevated HbA1c) after genetic counseling. CONCLUSION: In this case report, a patient with a homozygous variant in the GCK gene, who was diagnosed with DM after the infantile period, was presented, highlighting the fact that cases with homozygous variants in the GCK gene can, though rarely, present at a later age with a milder phenotype.

Reasons for adult referrals for genetic counseling at a genetics center in Izmir, Turkey: analysis of 8965 cases over an eleven-year period.

A limited numbers of published studies evaluate the referral reasons for genetic counseling services in the literature. These studies are focused on prenatal genetic counseling services, in particular, prenatal diagnosis. In order to provide the most effective and helpful genetic counseling services, genetics professionals need adequate knowledge about the profile of individuals referred for these services. In addition, physicians need increased awareness of the nature of genetic issues in order to make appropriate referrals. This study was intended to provide a descriptive analysis of the referral reasons of patients that received genetic counseling at a genetics center in Izmir, Turkey during an 11-year period. A total of 8965 records generated between 1998 and 2008 from one genetic center (which consists of The Department of Medical Genetics and Division of Pediatric Genetics) were evaluated retrospectively. Of these, 6,258 involved referrals for prenatal reasons, and 2,707 involved referrals for postnatal reasons. Both prenatal and postnatal records were further classified into more specific categories of referral reasons. The most common reason for genetic counseling among the prenatal patients was advanced maternal age (42.0%), followed by high risk results on prenatal biochemical screening tests such as second trimester double test [(serum concentration of alphafetoprotein (AFP), beta-human chorionic gonadotropin (beta-HCG)], triple test (serum concentration of AFP, beta-HCG, oestriol) and integrated test (26.5%). The most common indications for postnatal patients were recurrent miscarriages (28.2%) and infertility (19.7%). A significant increase in number of specific categories of referrals for genetic counseling was observed for the last 3 years after the establishment of the Medical Genetics Department. These data provide useful information about the frequency of referrals to the genetics department, and the feasibility of genetic services. Organization of genetic services and systematic procedures for genetic counseling and genetic testing may improve the public's awareness of genetics and ensure a high standard of patient care.

The relation between distant metastasis and genetic change type in stage IV lung adenocarcinoma patients at diagnosis.

INTRODUCTION: Brain metastasis prevalence is higher in patients with positive epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) and C-ROS oncogene 1 (ROS-1) fusion change in lung adenocarcinoma. OBJECTIVES: The purpose of our study is to investigate the relation between the genetic change type and the initial distant metastasis in stage IV lung adenocarcinoma patients with genetic changes. METHODS: The study was conducted between January 2007 and December 2018 in a retrospective fashion with patients who had lung cancer diagnosed as stage IV adenocarcinoma. The relation between genetic mutation change (EGFR, ALK or ROS-1) and distant metastasis was analysed. RESULTS: A total of 845 patients were included in the study. The median age was 62 (28-88). It was determined that lung and pleura metastases were more frequent at a significant level in patients with positive EGFR mutation (P = 0.032, P = 0.004, respectively). In patients with positive ALK fusion change, pleura metastasis was determined to be more frequent (P = 0.001). Multiple metastases were determined to be significantly more in patients with positive ALK fusion change than single metastasis (P = 0.02). CONCLUSION: In patients with EGFR mutant lung adenocarcinoma, lung and pleura metastasis is more frequent and pleura metastasis is more frequent in ALK positive adenocarcinoma. Additionally, multiple organ metastases are higher in ALK positive lung adenocarcinoma.

Variant ataxia-telangiectasia in a child presenting with laryngeal dystonia.

BACKGROUND: Dystonia is a common hyperkinetic movement disorder in children; however, making an early and definitive diagnosis of dystonia can sometimes be challenging for clinicians. CASE: Herein, we report a case of a 16 years-old girl presenting with laryngeal dystonia due to compound heterozygosity of a known pathogenic and a novel variant in the ATM gene. Serum alpha-fetoprotein level was elevated. Serum IgG, IgA, IgM and IgE levels were within normal range. Treatment with L-DOPA had no benefit. Her symptoms were dramatically improved by localized botulinum toxin injections. CONCLUSION: Mutations in the ATM gene show a wide phenotypic spectrum from severe classical early-onset ataxia-telangiectasia (A-T) to late-onset milder variant A-T. Our findings highlight the importance of recognizing laryngeal dystonia as one of the clinical signs of A-T.

The Efficiency of SNP-Based Microarrays in the Detection of Copy-Neutral Events at 15q11.2 and 11p15.5 Loci.

Prader-Willi, Angelman, Beckwith-Wiedemann, and Russell-Silver are imprinting syndromes. In this study, we aimed to compare the efficiency of single nucleotide polymorphism (SNP) microarray analysis with methylation-specific Multiplex ligation-dependent probe amplification (MS-MLPA) in the detection of uniparental disomy in these syndromes. The patient samples with regions of loss of heterozygosity (LOH), covering 15q11.2 and 11p15.5 critical loci, were analyzed with MS-MLPA to demonstrate the efficiency of SNP microarray in the detection of uniparental disomy (UPD). In a total of seven patients, LOH covering 15q11.2 and 11p15.5 critical loci was detected. Two (28.6%) of these seven patients showed aberrant methylation (suggesting UPD) in MS-MLPA. SNP microarray is a useful tool in the detection of LOH; however, it should be used with caution, since false-positive or false-negative LOH results can be obtained. Although methylation analysis is recommended as the first tier test in the diagnosis of most of the imprinting disorders, combining methylation analysis with SNP microarray can enhance our evaluation process.