Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications.

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling.

Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case.

Immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy.

Deletion of P2 promoter of GJB1 gene a cause of Charcot-Marie-Tooth disease.

X-linked Charcot-Marie-Tooth disease (CMT) is the second most common cause of CMT, and is usually caused by mutations in the gap junction protein beta 1 (GJB1) gene. This gene has nerve specific P2 promoter that work synergistically with SOX10 and EGR2 genes to initiate transcription. Mutation in this region is known to cause Schwann cell dysfunction.

Genetic heterogeneity of motor neuropathies.

Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.

Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).

Results: The prevalence of dHMN is 2.

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome.

Molecular genetic testing for the 11p15-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability.

Background: Inherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications.

Methods: We designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN.

Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations.

Phenotypic variability of TRPV4 related neuropathies.

Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot-Marie-Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene.

Potential prevention of thromboembolism by genetic counseling and testing for two common thrombophilia mutations.

Background/aim: Thrombophilia is a multifactorial predisposition for thromboembolism affecting about a tenth of any population. We investigated whether genetic counseling combined with molecular testing for two common dominant mutations (coagulation factor V Leiden and prothrombin G20210A) may increase prevention of venous thromboembolic incidents in individuals with a positive family history compared to the general population.

Patients And Methods: Mutation detection was carried out by Restriction Fragment Length Polymorphism analysis in DNA samples of 96 unrelated healthy Greeks (group A) who asked for genetic counseling for various reasons and had at least two relatives with thromboembolic incidents and 100 unrelated healthy Greeks (group B).

Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused by mutations in more than 40 genes. We investigated a four-generation family with 23 members affected by the axonal form (type 2), for which the common causes had been excluded by Sanger sequencing.

Easy, rapid, and cost-effective methods for identifying carriers of recurrent GJB2 mutations causing nonsyndromic hearing impairment in the Greek population.

A variety of techniques have been developed for screening the GJB2 gene for known and unknown mutations, especially the most common mutation in the Caucasian population, the c.35delG. Other mutations that have been so far characterized in the GJB2 gene seem to have different geographical distributions, and therefore there is an interest in identifying recurrent mutations specific for each population and developing easy and rapid screening techniques.

Prenatal diagnosis of achondroplasia presenting with multiple-suture synostosis: a novel association.

Objective: We report an atypical case of a fetus presenting with a combined achondroplasia and multiple craniosynostosis phenotype.

Methods: Sonographic monitoring in conjunction with molecular genetic analysis was performed in a 32-gestational weeks fetus.

Results: Sonographic findings were consistent with a diagnosis of achondroplasia associated with multiple-suture synostosis.

Prelingual nonsyndromic hearing loss in Greece. Molecular and clinical findings.

Mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) on chromosome 13q11 have been shown as a major contributor to prelingual, sensorineural, nonsyndromic deafness. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in Caucasian populations and is one of the most frequent disease mutations identified so far with highest carrier frequency of 3,5% in the Greek population. In a collaboration with the major referral centers for childhood deafness in Greece, patients were examined by an extensive questionnaire to exclude syndromic forms and environmental causes of deafness and by allele-specific PCR for the detection of the 35delG mutation.

Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism: clinical, cytogenetic and molecular analysis.

The clinical significance of trisomy 20 mosaicism detected prenatally remains uncertain due to the rarity of liveborn cases with inconsistent clinical findings, and lack of long-term follow-up and outcome. We describe a case of true trisomy 20 mosaicism in a liveborn girl with maternal uniparental isodisomy of chromosome 20 in the diploid blood cells. Trisomy 20 mosaicism was originally detected in amniotic fluid (98%) and was confirmed in the term placenta (100%), as well as in the blood (10%) and urine sediment (100%) of the neonate.

Prevalence of GJB2 mutations in prelingual deafness in the Greek population.

Objective: Mutations in the gene encoding the gap junction protein connexin 26 (GJB2) have been shown as a major contributor to prelingual, sensorineural, nonsyndromic, recessive deafness. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in Caucasian populations. The aim of our study was to determine the prevalence and spectrum of GJB2 mutations in prelingual deafness in the Greek population.

A simple and effective approach for detecting maternal cell contamination in molecular prenatal diagnosis.

The presence of maternal cells in fetal samples constitutes a serious potential source for prenatal misdiagnosis. Here we present our approach for detecting maternal cell contamination (MCC) at prenatal diagnosis for eight monogenic disorders (autosomal recessive: beta-thalassaemia, sickle-cell anaemia, cystic fibrosis, prelingual deafness; autosomal dominant: achondroplasia, Huntington disease, myotonic dystrophy, neurofibromatosis type I; X-linked: spinobulbar muscular atrophy). Our aim was to apply a simple and low-cost approach, which would easily and accurately provide information on the fetal tissue MCC status.

Prenatal diagnosis of two rare de novo structural aberrations of the Y chromosome: cytogenetic and molecular analysis.

Two rare de novo structural aberrations of the Y chromosome were detected during routine prenatal diagnosis: a satellited non-fluorescent Y chromosome (Yqs), the first de novo Yqs to be reported in a fetus, and a terminal deletion of the Y chromosome long arm del(Y)(q11). In both cases detailed cytogenetic and molecular analyses were undertaken. In the case of the Yqs it was demonstrated by fluorescence in situ hybridization (FISH) that the satellites were derived from chromosome 15.

Prenatal diagnosis of prelingual deafness: carrier testing and prenatal diagnosis of the common GJB2 35delG mutation.

Mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) on chromosome 13q11 (DFNB1 locus) have been shown as a major contributor to prelingual, non-syndromic, autosomal recessive deafness in Caucasian populations. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene and is one of the most frequent disease mutations identified to date. We have previously reported a carrier frequency of 35delG of 3.

Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness.

The GJB2 (connexin 26) gene, one of the major genes responsible for autosomal recessive deafness, has been investigated previously by a variety of techniques, including PCR-SSCP and sequencing of the entire gene for screening of unknown mutations, and allele-specific PCR, ASO, and PCR-mediated site-directed mutagenesis for the detection of the common mutation 35delG. Here, we present the development of a DGGE method for the characterization of the full spectrum of mutations in the GJB2 gene. The GJB2 cDNA and flanking sequences were amplified in three overlapping segments.

A widely applicable strategy for single cell genotyping of beta-thalassaemia mutations using DGGE analysis: application to preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) allows the selection of unaffected IVF embryos for transfer in couples that are at risk for transmitting genetic diseases. For monogenic diseases, polymerase chain reaction (PCR)-based diagnosis is usually performed on single blastomeres. In Greece, up to 10 per cent of the population are carriers for beta-thalassaemia and related haemoglobinopathies, and more than 20 pathological mutations in the beta-globin gene have been described.

Increased resistance to activated protein C and factor V Leiden in recurrent abortions. Review of other hypercoagulability factors.

Objective: To evaluate hereditary and acquired hemostatic abnormalities associated with recurrent spontaneous early (first-trimester) abortions.

Method: A group of 56 Greek women with two or more unexplained primary spontaneous abortions, and a reference group of 148 women without a history of recurrent abortions, were screened for hypercoagulability. A randomly selected population of first-trimester pregnant women was also chosen for factor V Leiden genetic screening.

Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in a Greek population of blood donors.

The pathogenesis of venous thrombosis involves the interaction of genetic and environmental factors. In order to estimate the frequency of the factor V Leiden, the prothrombin G20210A, and the MTHFR C677T mutations in the Greek population, we analyzed 160 healthy Greek blood donors by PCR amplification and detected allele frequencies of 2.5%, 2.