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Introduction: Non-syndromic polydactyly has been associated with pathogenic variants in 11 genes until today, including IQCE gene. More precisely, loss-of-function of IQCE is associated with the autosomal recessive disorder postaxial polydactyly type A7 (PAPA7, MIM #617642). Case Presentation: A 3-year-old female patient was referred to our genetics department with postaxial polydactyly, syndactyly, brachydactyly, and hypoplastic teeth. Through whole-exome sequencing (WES), a pathogenic IQCE variant was identified (c.895_904del) in the homozygous state, which adequately explained the disease phenotype of our patient. However, copy number variant (CNV) analysis from WES data, using ExomeDepth, revealed a novel, likely pathogenic large deletion involving IQCE genomic regions (DEL:chr7:2606751_2641098) encompassing exons 2–18 of the gene. Conclusion: IQCE gene codes for a 695-amino acid protein located at the base of the primary cilia that positively regulates the Hedgehog signaling pathway. This case report represents the first description of a large deletion in IQCE and indicates that implementation of ExomeDepth in routine WES analysis can contribute valuable information toward elucidating the correct etiology of rare genetic diseases, increasing the diagnostic yield, and minimizing the need for additional tests.

ATP6V1B2 pathogenic variants are linked with variable phenotypes, such as dominant deafness-onychodystrophy syndrome (DDOD), autosomal dominant Zimmermann-Laband syndrome type 2 (ZLS2), and some cases of DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [ID], and seizures). Epilepsy was first linked to ATP6V1B2, when the p.(Glu374Gln) missense variant was detected in a patient with ID and seizures, but without characteristic features of DDOD or ZLS2 syndromes. We herein report a novel pathogenic ATP6V1B2:p.Glu374Gly variant detected in an adult patient with ID and myoclonic-atonic seizures. The (re)occurrence of different variants affecting the same highly conserved hydrophilic glutamic acid on position 374 of the V-proton ATPase subunit B, indicates a potential novel pathogenic hotspot and a critical role for the specific residue in the development of epilepsy. ATP6V1B2 gene defects should be considered when analyzing patients with epilepsy, even in the absence of most cardinal features of DDOD, DOORS, or ZLS such as deafness, onychodystrophy, and osteodystrophy.

Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis. This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders. Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy. Emerging advances of next-generation technologies and ‘in silico’ analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, known as Rasopathies, due to the implication of genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease's recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and next-generation sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are as follows: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype-phenotype analysis showed statistically significant differences in craniofacial dysmorphisms (p = 0.005) and pulmonary valve stenosis (PS) (p 0.001) frequencies between patients harbouring a pathogenic variant and patients without pathogenic variant in any of the tested genes. Patients with at least a pathogenic variant had 6.71 times greater odds to develop PS compared to pathogenic variant-negative patients (OR = 6.71, 95%; CI = (2.61, 17.27)). PTPN11 positive patients showed higher frequency of epicanthal folds (p = 0.004), ptosis (p = 0.001) and coarseness (p = 0.001) and lower frequency of neurological findings (p = 0.006), compared to patients carrying pathogenic variants in other genes.Craniofacial dysmorphism and PS prevail among pathogenic variant positive compared to pathogenic variant negative NS and NS-like patients while neurological defects are less common in PTPN11-affected NS patients compared to patients harbouring pathogenic variants in other genes. The significant prevalence of the Ras/MAPK pathogenic variants (17.4%), other than PTPN11, in Greek NS patients, highlights the necessity of a wider spectrum of molecular diagnosis.• Noonan syndrome (NS) has been associated with pathogenic variants in molecules-components of the Ras/MAPK pathway. • Clinical and genetic description of NS patients worldwide helps establishing personalized monitoring.• NS and NS-like mutational rate in Greece reaches 50% with pathogenic variants identified mostly in PTPN11 (32.5%), RIT1 (6%) and SOS1 (4.7%) genes. • The risk for pulmonary stenosis increases 6.71-fold in NS patients with a pathogenic variant compared to patients without genetic alterations.

Pathogenic KMT2E variants underly O'Donnell-Luria-Rodan syndrome, a recently described neurodevelopmental disorder characterized by global developmental delay, variable degrees of intellectual disability, and subtle facial dysmorphism. Less common findings include autism, seizures, gastrointestinal (GI) problems, and abnormal head circumference. Occurrence of mostly truncating variants as well as the similar phenotype observed in individuals with deletions spanning KMT2E suggest haploinsufficiency of this gene as a common mechanism for the disorder, while a gain-of-function or dominant-negative effect cannot be ruled out for some missense variants. Deletions reported in the literature encompass several additional known or presumed haploinsufficient genes, thus leading to more complex phenotypes. Here, we describe a male with antenatal onset hydronephrosis, hypotonia, global developmental delay, prominent GI symptoms as well as facial dysmorphism. Chromosomal microarray revealed a 239-kb de novo microdeletion spanning KMT2E and LHFPL3. Clinical presentation of our proband, harboring one of the smallest deletions of the region confirms the core features of this disorder, suggests GI symptoms as a prominent finding in affected individuals while expanding the phenotypic spectrum to abnormalities of the urinary tract.

BACKGROUND/OBJECTIVES:Optic-pathway-glioma(OPG) represents the most common central-nervous tumor in children with neurofibromatosis type-1(NF1), occurring at an incidence of 15-20%. It is estimated that 1/3 of NF1 patients(pts) with OPG will need treatment. DESIGN-METHODS:We performed a retrospective-review of all NF1-pts examined in the First Hellenic Multidisciplinary-Clinic – Center of Expertise for Neurocutaneous-disorders. Gender, age, MRI-radiological and ophthalmological findings, presence of OPG, management and outcome were analyzed. RESULTS:Since the establishment of the Clinic in 2016, 198pts with clinical diagnosis of NF1 based on NIH1988-criteria were evaluated and of them, 165(73 females, median age:5.5y, range:0.3-17.1y), who had imaging studies were included in this analysis. Eighty three pts(50.3%) had NF1-positive genetic-testing and 45NF1-family-history(27.3%). Imaging-findings from optic pathway were found in 55/165pts(28females). Percentage of pts with findings were 51.7% for 10y, respectively. The median age of their first brain-MRI imaging was 2.82y. Upon 1stMRI-imaging, 70.9% presented thickness of the optic nerves(ON)(25,4%bilateral, 20% optic chiasm,18.1% right ON, 10.0% left ON), 14.5%ON-tortuosity, 38.1%OPG(43,5% in the optic-chiasm) and 34.5% contrast enhancement. Of notice, 14pts presented an OPG after a median follow-up time of 1.79y. According to LGG2004-protocol indications for treatment, only 15/55pts had to be treated(27,2%, 5pts with family history, 33.3% between 5-10y). Severe vision-loss with need for immediate start of treatment upon 1stMRI imaging was found in 4pts, of whom 75% had family-history and first evaluation after the 5th year of age. Of notice, only 2pts

Neurofibromatosis Type 1 (NF1) is caused by mutations of the NF1 gene. The aim of this study was to identify the genetic causes underlying the disease, attempt possible phenotype/genotype correlations and add to the NF1 mutation spectrum. A screening protocol based on genomic DNA was established in 168 patients, encompassing sequencing of all coding exons and adjoining introns using a custom targeted next generation sequencing protocol and subsequent confirmation of findings with Sanger sequencing. MLPA was used to detect deletions/duplications and positive findings were confirmed by RNA analysis. All novel findings were evaluated according to ACMG Standards and guidelines for the interpretation of sequence variants with the aid of in-silico bioinformatic tools and family segregation analysis. A germline variant was identified in 145 patients (86%). In total 49 known and 70 novel variants in coding and non-coding regions were identified. Seven patients carried whole or partial gene deletions. NF1 patients, present with high phenotypic variability even in cases where the same germline disease causing variant has been identified. Our findings will contribute to a better knowledge of the genetic causes and the phenotypic expression related to the disease.

About 6000 to 7000 different rare disorders with suspected genetic etiologies have been described and almost 4500 causative gene(s) have been identified. The advent of next-generation sequencing (NGS) technologies has revolutionized genomic research and diagnostics, representing a major advance in the identification of pathogenic genetic variations. This study presents a 3-year experience from an academic genetics center, where 400 patients were referred for genetic analysis of disorders with unknown etiology. A phenotype-driven proband-only exome sequencing (ES) strategy was applied for the investigation of rare disorders, in the context of optimizing ES diagnostic yield and minimizing costs and time to definitive diagnosis. Overall molecular diagnostic yield reached 53% and characterized 243 pathogenic variants in 210 cases, 85 of which were novel and 148 known, contributing information to the community of disease and variant databases. ES provides an opportunity to resolve the genetic etiology of disorders and support appropriate medical management and genetic counseling. In cases with complex phenotypes, the identification of complex genotypes may contribute to more comprehensive clinical management. In the context of effective multidisciplinary collaboration between clinicians and laboratories, ES provides an efficient and appropriate tool for first-tier genomic analysis.

About 6,000 to 7,000 different rare disorders with suspected genetic etiologies have been described and in almost 4,500 of them the causative gene(s) have been identified. The advent of Next-Generation Sequencing (NGS) technologies has revolutionized genomic research and diagnostics, representing a major advance in identification of pathogenic genetic variations. WES facilitates a faster and more cost-effective route for definite diagnosis of rare genetic disorders, minimizing previous “diagnostic odysseys” for the patients. Due to the limitation that WES is not reimbursed in Greece, we aimed to minimize cost per patient/family through applying WES in the proband, followed by targeted family segregation studies when necessary. Furthermore, for variant filtration and interpretation we applied a phenotypic-driven strategy in close collaboration with clinical geneticists or referring clinicians. In this study we report the clinical application of WES in the diagnosis of 162 cases referred to investigate patients with undiagnosed genetic disorders. The overall molecular diagnostic yield reached 52.5%. Our experience as an academic diagnostic laboratory using WES, although limited to the last two years, allowed characterization of 94 pathogenic variants in 85 positive cases, 48 of which were novel, contributing information to the community of disease and variant databases.

X-linked myotubular myopathy (XLMTM) is a rare inherited neuromuscular disorder associated with mutations in the MTM1 gene on the Xq28 region. We report a severely affected girl with XLMTM, caused by maternally inherited 661 kb Xq28 microduplication identified by chromosomal microarray analysis and confirmed also on DNA from muscle biopsy with a custom-designed X-chromosome-specific microarray. X-inactivation analysis revealed a skewed inactivation pattern on the proband's muscle biopsy. Muscle biopsy histopathology was indicative of increased variability in fiber diameter, marked and diffuse endomysial proliferation of adipose and connective tissues, as well as predominance of type 1 fibers.

Given the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care.Subjects and Methods: Retrospective analysis of a cohort of 157 pa...

Background Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome that can be accompanied by disordered steroidogenesis, and is mainly caused by mutations in the POR gene, inherited in an autosomal recessive manner. Here we report the prenatal and postmortem findings of three sibling fetuses with ABS as a result of compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in the POR gene. Methods Prenatal ultrasound and postmortem examination were performed in three sibling fetuses with termination of pregnancy at 22, 23, and 17 weeks of gestation, respectively. Molecular analysis of fetus 2 and 3 included (a) bidirectional sequencing of exon 8 of the POR gene after amplification of the specific locus by polymerase chain reaction, to detect single nucleotide variants (SNVs) and (b) high resolution comparative genomic hybridization (CGH) positive single nucleotide polymorphism array CGH (aCGH) analysis to detect copy number variants (CNVs), copy neutral areas of loss of heterozygosity and uniparental disomy. Results The diagnosis of ABS was suggested by the postmortem examination findings. The combination of the POR gene molecular analysis and aCGH revealed a compound heterozygous genotype of a maternal SNV (p.A287P) and a paternal CNV (NC_000007.13:g.(?_75608488)_(75615534_?)del). Conclusion To the best of our knowledge, these sibling fetuses add to the few reported cases of ABS, caused by a combination of a SNV and a CNV in the POR gene. The detailed description of the pathologic and radiographic findings of second trimester fetuses affected with ABS adds novel knowledge concerning the early ABS phenotype, in lack of previous relevant reports. Birth Defects Research (Part A) 106:536–541, 2016. © 2016 Wiley Periodicals, Inc.

Chromosomal microarray analysis (CMA) is currently considered a first-tier diagnostic assay for the investigation of autism spectrum disorders (ASD), developmental delay and intellectual disability of unknown etiology. High-resolution arrays were utilized for the identification of copy number variations (CNVs) in 195 ASD patients of Greek origin (126 males, 69 females). CMA resulted in the detection of 65 CNVs, excluding the known polymorphic copy number polymorphisms also found in the Database of Genomic Variants, for 51/195 patients (26.1%). Parental DNA testing in 20/51 patients revealed that 17 CNVs were de novo, 6 paternal and 3 of maternal origin. The majority of the 65 CNVs were deletions (66.1%), of which 5 on the X-chromosome while the duplications, of which 7 on the X-chromosome, were rarer (22/65, 33.8%). Fifty-one CNVs from a total of 65, reported for our cohort of ASD patients, were of diagnostic significance and well described in the literature while 14 CNVs (8 losses, 6 gains) were characterized as variants of unknown significance and need further investigation. Among the 51 patients, 39 carried one CNV, 10 carried two CNVs and 2 carried three CNVs. The use of CMA, its clinical validity and utility was assessed.

Background Retinal dystrophies are a clinically and genetically heterogeneous group of disorders which affect more than two million people worldwide. The present study focused on the role of the ABCA4 gene in the pathogenesis of hereditary retinal dystrophies (autosomal recessive Stargardt disease, autosomal recessive cone-rod dystrophy, and autosomal recessive retinitis pigmentosa) in patients of Greek origin. Materials and methods Our cohort included 26 unrelated patients and their first degree healthy relatives. The ABCA4 mutation screening involved Sanger sequencing of all exons and flanking regions. Evaluation of novel variants included sequencing of control samples, family segregation analysis and characterization by in silico prediction tools. Twenty five patients were also screened for copy number variations by array-comparative genomic hybridization. Results Excluding known disease-causing mutations and polymorphisms, two novel variants were identified in coding and non-coding regions of ABCA4. Array-CGH analysis revealed two partial deletions of USH2A and MYO3A in two patients with nonsyndromic autosomal recessive retinitis pigmentosa. Conclusions The ABCA4 mutation spectrum in Greek patients differs from other populations. Bioinformatic tools, segregation analysis along with clinical data from the patients seemed to be crucial for the evaluation of genetic variants and particularly for the discrimination between causative and non-causative variants., Highlights • Sixteen known pathological genetic variants were identified in ABCA4 gene in Greek patients with retinal dystrophies. • Two novel variants were found in patients with Stargardt’s disease and cone-rod dystrophy respectively. • Two reported mutations in Stargardt's patients were identified in retinitis pigmentosa and cone-rod dystrophy patients. • The mutations p.Gly1961Glu and p.Ala1038Val, which are common in other populations, where also found in our cohort consisted of 26 Greek patients. • Array-comparative genome hybridization revealed large deletions in two out of the 25 cases studied.

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field. This work was supported by TREAT-NMD operating grants, FP6 LSHM-CT-2006-036825, 20123307 UNEW FY2013 and AFM 16104. Further support came from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics) and Medical Research Council UK (reference G1002274, grant ID 98482). Sí

Constitutional microdeletions affecting 3q13.2q13.31 are rare and attempts for genotype–phenotype correlations have only recently been made in a cohort of 28 patients. The major phenotypic features of this rare syndrome are hypotonia, developmental delay, and facial anomalies. In this study, we report on a male infant with a novel reciprocal 3.671 Mb microduplication at the genomic region 3q13.2q13.31 associated with dysmorphic features and multiple congenital anomalies. The current patient was investigated by high-resolution array comparative genomic hybridization (aCGH). This is the first report of a microduplication 3q13.2q13.31 that shares a lot of common clinical features with those carrying the microdeletion. The 3q13.2q13.31 duplicated region in our patient contains nine dosage sensitive genes, amongst them the genes ATG3, CCDC80, KIAA2018, NAA50, ZDHHC23, DRD3, ZBTB20, GAP43, LSAMP. As it is the case for many other well-described reciprocal deletion/duplication syndromes, some have very different clinical features (Williams–Beuren deletion syndrome, WBS/WBS triplication) [Somerville et al. (2005); N Engl J Med 353:1694–1701], while others share similar phenotypic features (22q11.2 microdeletion/microduplication) [Portnoi (2009); Eur J Med Genet 52:88–93]. In conclusion, we describe the main phenotypic features of a possibly novel microduplication 3q13.2q13.31 syndrome. Additionally five of the dosage-sensitive genes and BOC gene are suggested to be responsible for the main phenotypic features. Evaluation of multiple patients with the microduplication is needed for full delineation of this syndrome. © 2013 Wiley Periodicals, Inc.

gene. The first patient was homozy-gous for c.1096A>C (p.S366R) mutation in exon 9. Thesecond patient had a complex genotype involving threemutations, the c.1096A>C (p.S366R), a novel 2 bp dele-tion c.649_650delGT and the previously reported c.791C>G(p.P264R); the last two have been inherited in

A 28-month-old girl with dysmorphic craniofacial features, microcephaly, hypotonia, psychomotor retardation, failure to thrive and gastrointestinal problems was referred for clinical evaluation. Array-CGH analysis revealed one of the smallest de novo microdeletions on chromosome 16q21q22.1, 2.03 Mb in size. Advanced molecular analysis contributes to more precise genotype-phenotype correlation and accurate definition of the breakpoints in the deleted/duplicated regions.

High resolution oligonucleotide array Comparative Genome Hybridization technology (array-CGH) has greatly assisted the recognition of the 1p36 contiguous gene deletion syndrome. The 1p36 deletion syndrome is considered to be one of the most common subtelomeric microdeletion syndromes and has an incidence of ~1 in 5000 live births, while respectively the "pure" 1p36 microduplication has not been reported so far. We present seven new patients who were referred for genetic evaluation due to Developmental Delay (DD), Mental Retardation (MR), and distinct dysmorphic features. They all had a wide phenotypic spectrum. In all cases previous standard karyotypes were negative. Array-CGH analysis revealed five patients with interstitial 1p36 microdeletion (four de novo and one maternal) and two patients with de novo reciprocal duplication of different sizes. These were the first reported "pure" 1p36 microduplication cases so far. Three of our patients carrying the 1p36 microdeletion syndrome were also found to have additional pathogenetic aberrations. These findings (del 3q27.1; del 4q21.22-q22.1; del 16p13.3; dup 21q21.2-q21.3; del Xp22.12) might contribute to the patients' severe phenotype, acting as additional modifiers of their clinical manifestations. We review and compare the clinical and array-CGH findings of our patients to previously reported cases with the aim of clearly delineating more accurate genotype-phenotype correlations for the 1p36 syndrome that could allow for a more precise prognosis.

BACKGROUND Cat-Eye syndrome (CES) with teratoma has not been previously reported. We present the clinical and molecular findings of a 9-month-old girl with features of CES and also a palpable midline neck mass proved to be an extragonadal mature teratoma, additionally characterized by array comparative genomic hybridization (aCGH). RESULTS High resolution oligonucleotide-based aCGH confirmed that the supernumerary marker chromosome (SMC) derived from chromosome 22, as was indicated by molecular cytogenetic analysis with fluorescence in situ hybridization (FISH). Additionally, aCGH clarified the size, breakpoints, and gene content of the duplication (dup 22q11.1q11.21; size:1.6 Mb; breakpoints: 15,438,946-17,041,773; hg18). The teratoma tissue was also tested with aCGH, in which the CES duplication was not found, but the analysis revealed three aberrations: del Xp22.3 (108,864-2788,689; 2.7 Mb hg18), dup Yp11.2 (6688,491-7340,982; 0.65 Mb, hg18), and dup Yq11.2q11.23 (12,570,853-27,177,133; 14.61 Mb, hg18). These results indicated 46 XY (male) karyotype of the teratoma tissue, making this the second report of mature extragonadal teratoma in a female neonate, probably deriving from an included dizygotic twin of opposite sex (fetus in fetu). CONCLUSIONS Our findings extend the phenotypic spectrum of CES syndrome, a disorder with clinical variability, pointing out specific dosage-sensitive genes that might contribute to specific phenotypic features.

Contains fulltext : 152777.pdf (Publisher’s version ) (Open Access) We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.

Congenital heart diseases (CHDs) are often associated with other congenital anomalies, dysmorphic features, and developmental delay, and only a few cases of chromosomal abnormalities are detected by conventional cytogenetic techniques. The microarray comparative genomic hybridization (CGH) analysis allows the identification of submicroscopic genomic rearrangements. During the past 3 y, 55 of 330 patients referred for array CGH had CHD of unknown etiology plus at least one additional indication of abnormal chromosomal phenotype. High-resolution 1 × 244K or 4 × 180K Agilent arrays were used in this study (average resolution 7–13 kb). Copy-number variations were detected in 37 of 55 patients, and in 29 of 37 patients there were genes that have been associated with CHD. All 37 patients had at least one additional phenotypic abnormality: 30 of 37 had one or more other congenital anomalies, 23 of 37 had dysmorphic features, 16 of 37 had intellectual disability, 13 of 37 had abnormal magnetic resonance imaging, 10 of 37 had hypotonia, and 7 of 37 had seizures. In 9 of 55 patients, unexpected genomic rearrangements in relation to their phenotype were identified. In patients with CHD and at least one additional indication of abnormal chromosomal phenotype, array CGH analysis could detect possible submicroscopic chromosomal abnormalities and provide proper genetic counseling.

BACKGROUND: Pelizaeus-Merzbacher disease (PMD) is a recessive, X-linked leukoencephalopathy attributed to impaired myelination during central nervous system development, caused by defects in the proteolipid protein 1 (PLP1) gene. PMD presents clinical variability, ranging from the severe connatal form to the classic form. CASES: We report the clinical and molecular findings of two affected males, three carrier females, and an aborted male fetus with familial PMD. The two male probands presented with severe PMD phenotype and intellectual disability. High-resolution oligonucleotide-based array comparative genomic hybridization (aCGH) identified an Xq22.2 duplication of 320.6 kb (102641391-102961998, hg18), including the PLP1 gene and surrounding chromosomal region. Postmortem examination of the aborted fetus at 25 weeks’ gestation showed focal subcortical white matter degeneration, focal gliosis, and cerebellar atrophy. CONCLUSIONS: Genotype-phenotype correlation is provided. In the connatal form of PMD, leukodystrophy and cerebellar atrophy can occur antenatally and be established at 25 weeks’ gestation. The observation of degenerative brain lesions occurring before the onset of subcortical myelination suggests that the PLP1 gene has a more complex role in human brain development, exceeding its structural function in myelin formation. Birth Defects Research (Part A) 94:494–498, 2012. 2012 Wiley Periodicals, Inc.

The recognition of the 17q21.31 microdeletion and microduplication syndrome has been facilitated by high resolution oligonucleotide array comparative genome hybridization technology (aCGH). Molecular analysis of the 17q21.31 microdeletion/duplication syndrome demonstrated a critical region involving at least six genes, including STH and MAPT. The 17q21.31 microdeletion syndrome has an incidence of 1 in 16,000 births, while the microduplication 17q21.31 has been reported so far in only five patients. In general, phenotypes associated with 17q21.31 microduplication seem to be milder than those associated with the microdeletion. Here, we present four patients who have been referred for genetic evaluation by clinical geneticists due to developmental delay and minor congenital abnormalities. Previous standard karyotypes were negative, while aCGH analysis revealed three patients with 17q21.31 microdeletion and one with the respective microduplication, being the sixth reported case so far. Most importantly one of the microdeletion cases involves only partial MAPT gene deletion while leaving the STH gene intact. Two of our patients, one with the 17q21.31 microdeletion and another with the respective microduplication, carried additional clinically relevant microdeletions (del Xq21.31 and del 15q11.2, respectively), possibly modifying their phenotype.

Noonan syndrome (NS) is a common multiple congenital anomaly entity, the diagnosis of which, on clinical grounds, is based on a comprehensive scoring system in order to select patients for molecular confirmation. Our aim was to evaluate the phenotypic characteristics in the light of PTPN11 mutations. The study revealed 80 patients who were referred with initial indication of NS or Noonan-like syndrome (NLS) and further assessed by a clinical geneticist; 60/80 index patients, mean age 5.9 ± 5.3 years, fulfilled the NS criteria. Molecular analysis of PTPN11 gene (exons and their flanking regions) of the total population revealed mutations in 17/80 patients, all belonging in the group of the patients screened with the scoring system. All mutations were heterozygous missense changes, mostly clustering in exon 3 (8/17), followed by exons 13 (3/17), 8 (2/17), 7 (2/17), 2 (1/17) and 4 (1/17). We conclude that (a) most of our clinically diagnosed NS cases were sporadic (b) PTPN11 analysis should be limited to those fulfilling the relevant NS criteria (c) Cardiovascular evaluation should comprise all NS patients, while pulmonary stenosis, short stature, and thorax deformities prevailed among those with PTPN11 mutations.

The Clinical Implication of Array-CGH (Agilent 244K and 4X180K) Analysis in Pediatric Services

Background Beta-thalassaemia major (b-TM) has been defined as a combination of chronic hemolytic anemia, iron storage disease and myocarditis, and it has been associated with premature death especially due to heart failure. To the best of our knowledge the status of blood lipids in these patients has rarely been investigated. Thus, we assessed the levels of lipids and lipoproteins in a sample of cardiovascular disease free adult men and women with b-TM.

Background This is a case with multiple chromosomal aberrations which are likely etiological for the observed psychiatric phenotype consisting of attention deficit hyperactivity and conduct disorders. Case presentation We report on an 11 year-old boy, admitted to the pediatric hospital for behavioral difficulties and a delayed neurodevelopmental trajectory. A cytogenetic analysis and high-resolution microarray comparative genomic hybridization (CGH) analysis was performed. The cytogenetic analysis revealed 47,XYY syndrome, while CGH analysis revealed an additional duplication and two deletions. The 7q11.23 duplication is associated with speech and language delay and behavioral symptoms, a 20q13.33 deletion is associated with autism and early onset schizophrenia and the 11p15.5 microdeletion is associated with developmental delay, autism, and epilepsy. The patient underwent a psychiatric history, physical examination, laboratory testing, and a detailed cognitive, psychiatric, and occupational therapy evaluation which are reported here in detail. Conclusions In the case of psychiatric patients presenting with complex genetic aberrations and additional psychosocial problems, traditional psychiatric and psychological approaches can lead to significantly improved functioning. Genetic diagnostic testing can be highly informative in the diagnostic process and may be applied to patients in psychiatry in case of complex clinical presentations.