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Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing. In all seven cases, a disruption of at least one gene was found. In two patients, the phenotypic impact of the disrupted genes is well known (NFIA, ATP7A). In five patients, the aberration damaged genes: PARD3, EPHA6, KLF13, STK24, UBR3, MLLT10 and TLE3, whose influence on the human phenotype is poorly understood. In particular, our results suggest novel candidate genes for retinal degeneration with anophthalmia (EPHA6), developmental delay with speech impairment (KLF13), and developmental delay with brain dysembryoplastic neuroepithelial tumor (UBR3). In conclusion, identification of the exact structure of symptomatic BCTs using next generation sequencing is a viable method for both diagnosis and finding novel disease candidate genes in humans.

Rare multiple congenital malformations/developmental disorders are challenging in clinical diagnosis. The introduction of next-generation sequencing (NGS) has revolutionized this diagnostic by offering multigene panels or whole-exome sequencing. However, if there is no possibility to perform NGS or if we are facing prenatal ultrasound results, clinical diagnostics is even more difficult. For a selected group of congenital metabolic disorders, resulting from defects in cholesterol biosynthesis (called cholesterolopathies), application of gas chromatography-mass spectrometry (GS-MS) may provide or orientate diagnostics. The most common of these is Smith-Lemli-Opitz syndrome (SLOS), but in this publication, we also want to introduce other cholesterolopathies and draw attention to the possibility of non-invasive prenatal diagnosis of SLOS.

Background The defects in DNA repair genes are potentially linked to development and response to therapy in medulloblastoma. Therefore the purpose of this study was to establish the spectrum and frequency of germline variants in selected DNA repair genes and their impact on response to chemotherapy in medulloblastoma patients. Methods The following genes were investigated in 102 paediatric patients: MSH2 and RAD50 using targeted gene panel sequencing and NBN variants (p.I171V and p.K219fs*19) by Sanger sequencing. In three patients with presence of rare life-threatening adverse events (AE) and no detected variants in the analyzed genes, whole exome sequencing was performed. Based on combination of molecular and immunohistochemical evaluations tumors were divided into molecular subgroups. Presence of variants was tested for potential association with the occurrence of rare life-threatening AE and other clinical features. Results We have identified altogether six new potentially pathogenic variants in MSH2 (p.A733T and p.V606I), RAD50 (p.R1093*), FANCM (p.L694*), ERCC2 (p.R695C) and EXO1 (p.V738L), in addition to two known NBN variants. Five out of twelve patients with defects in either of MSH2, RAD50 and NBN genes suffered from rare life-threatening AE, more frequently than in control group (p = 0.0005). When all detected variants were taken into account, the majority of patients (8 out of 15) suffered from life-threatening toxicity during chemotherapy. Conclusion Our results, based on the largest systematic study performed in a clinical setting, provide preliminary evidence for a link between defects in DNA repair genes and treatment related toxicity in children with medulloblastoma. The data suggest that patients with DNA repair gene variants could need special vigilance during and after courses of chemotherapy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3211-y) contains supplementary material, which is available to authorized users.

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways. Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Background: Chromosomal duplications involving 17p13.3 have recently been defined as a new distinctive syndrome with several diagnosed patients. Some variation is known to occur in the breakpoints of the duplicated region and, consequently, in the phenotype as well. Aims: We report on a patient, the fifth to our knowledge, a 4-year-old girl with a pure de novo subtelomeric 17p13.2-pter duplication. She presents all of the facial features described so far for this duplication and in addition, a unilateral palmar transversal crease and oculocutaneous albinism which has not been reported previously. Methods: A detailed molecular description of the reported aberration and correlation with the observed phenotypical features based on a literature review. We discuss the possible molecular etiology of albinism in regard to the mode of inheritance. Conclusion: The new data provided here may be useful for further genotype correlations in syndromes with oculocutaneous albinism, especially of autosomal dominant inheritance.

WOS: 000327800400004, PubMed ID: 23906836, Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1211A, 01GM1211B]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S398]; ERARE-ANR CraniRareFrench National Research Agency (ANR); German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01GS08167]; DFGGerman Research Foundation (DFG) [BO 1955/2-3, WU 314/6-2]; Volkswagen FoundationVolkswagen [86042]; Telethon ItalyFondazione Telethon [GTB12001], This work was part of the CRANIRARE-2 Network funded by the German Federal Ministry of Education and Research (BMBF) (01GM1211A to B. W., 01GM1211B to D. W.), the TUBITAK (112S398 to H. K.) and ERARE-ANR CraniRare to S. L. This work was also funded by a grant (MRNET) from the German Federal Ministry of Education and Research (01GS08167 to D. W.), by DFG grants (BO 1955/2-3 and WU 314/6-2 to S. B. and D. W.) and by the Volkswagen Foundation (ref 86042 to A. W.). The biobank "Cell lines and DNA bank of Rett syndrome, X linked Mental Retardation and other genetic diseases", member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, provided us with specimens.

Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.

The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders. © 2011 The American Society of Human Genetics.

Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is associated with c.1528G>C substitution in the HADHA gene, since most patients have the prevalent mutation on at least one allele. As it is known that the disease is relatively frequent in Europe, especially around the Baltic Sea, and that the majority of Polish LCHADD patients originate from the coastal Pomeranian province, partly inhabited by an ancient ethnic group, the Kashubians, we aimed to determine the carrier frequency of the prevalent HADHA mutation in various districts of Poland with special focus on the Kashubian district. A total of 6,854 neonatal dried blood samples from the entire country, including 2,976 Pomeranian neonates of Kashubian origin, were c.1528G>C genotyped. Fifty-nine heterozygous carriers for the prevalent c.1528G>C substitution (41 Pomeranian children) were detected in the studied group. Our data reveal a geographically skewed distribution of the c.1528C allele in the Polish population; in the northern Pomeranian province the carrier frequency is 1:73, which is the highest frequency ever reported, whereas in the remaining regions it is 1:217. Hence, the incidence of LCHADD in Poland is predicted to be 1:118,336 versus 1:16,900 in the Pomeranian district. Despite the relative rarity of the disease, screening for LCHADD in neonates born in the northern part of Poland, especially those of Kashubian origin, is justified. Our data allow us to suggest a probable Kashubian origin of the prevalent c.1528G>C mutation.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder with especially high mortality and uncertain long-term outcome. The aim of the study was to analyze the influence of diagnostic approach on survival in 59 affected children. Referral to a metabolic center was replaced over time by urine/blood testing in centralized metabolic laboratory (selective screening) and by pilot tandem mass spectrometry newborn screening (NBS). Molecular analysis revealed the prevalent mutation in the HADHA gene in all 58 examined cases. Twenty patients died. The number of detections and number of deaths were respectively 9 and 4 (44%) in the patients recognized by differential diagnosis, 28 and 9 (32%) - by selective screening, and 11 and 1 (9%) - by NBS. In 80% of cases the death occurred before or within 3 weeks from the identification. Urgent and active metabolic service remarkably influenced the surviving. The current age of 39 survivors is 0.5 to 23 yrs (mean 7.2 yrs). The disease frequency estimated on the patients number was 1: 115 450, whereas in the pilot NBS - 1: 109 750 (658 492 neonates tested). Interestingly, the phenylalanine level in asymptomatic neonates frequently exceeded the cut-off values. Conclusions: 1) Urgent metabolic intervention decreases mortality of LCHAD-deficient patients, but the prognosis is still uncertain. 2) Emergent metabolic reporting and service are crucial also for the survival of neonates detected by NBS. 3) The nationwide selective screening appeared efficient in LCHADD detection in the country. 4) Transient mild hyperphenylalaninaemia may occur in LCHAD-deficient newborns.

Editor—Nijmegen breakage syndrome (NBS) (OMIM 251260) is a rare autosomal recessive condition. The major manifestations include microcephaly, a distinct facial appearance, growth retardation, recurring infections owing to combined immunodeficiency, spontaneous chromosomal instability (with characteristic rearrangements of chromosomes 7 and 14), hypersensitivity to ionising radiation, and a very high predisposition to lymphoid malignancy. The immunological, cytogenetic, and cell biological findings are very similar to those in ataxia telangiectasia (AT); however, NBS patients lack the neurocutaneous manifestations of AT, as well as a raised serum α-fetoprotein (AFP).1-3Recently, the gene mutated in NBS has been cloned. The NBS1 gene is located on chromosome 8q21 and encodes a protein called nibrin, a member of the hRad50/hMre11 protein complex involved in DNA double strand break processing.4 ,5 NBS is quite a rare disease with about 80 patients ascertained world wide, including 50 Polish. The vast majority of NBS patients are of Slavic origin and carry a common founder mutation 657del5 in exon 6.4 We report on a Polish patient with Nijmegen breakage syndrome presenting an atypical clinical picture with the absence of microcephaly and the presence of a congenital heart defect and preaxial polydactyly. To the best of our knowledge, no NBS patient without microcephaly or with congenital cardiac disease has ever been reported and preaxial polydactyly has been observed in only two other cases.3 The proband, a girl, was born at term by spontaneous vertex delivery after an uneventful pregnancy. Birth weight was 3500 g, length 55 cm, occipitofrontal circumference (OFC) 35.5 cm, and chest circumference 33 cm, all above the 50th centile. Apgar score was 9 at one minute. Clinical investigation at birth showed preaxial polydactyly of the right hand, which has been surgically corrected. No other malformations were noted at that time. She was …

We report a case of a 19-year-old male with the cardinal features of the Kabuki syndrome (KS) and, in addition, with severe immunodeficiency. Finding immune deficiency in a KS patient, prompted us to determine whether this association was related to a deletion within the DiGeorge chromosomal region. Fluorescence in situ hybridization (FISH) with the Oncor probe N25(D22S75) revealed no deletion of 22q11.2 in the patient.

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.

The DYSCERNE Network of Centres of Expertise for dysmorphology (http://www.dyscerne.org), is developing clinical management guidelines for Williams (WS), Angelman (AS), Noonan (NS) and Kabuki (KS) syndromes. An initial scoping exercise identified these conditions as rare, complex, multi-system disorders, for which it was felt that affected patients, families and health/social care professionals would benefit from access to up-to-date evidence based management guidelines. Published evidence from which to develop management recommendations for these conditions is very limited, and devising a systematic and robust methodology has been challenging. Our approach is based on the Scottish Intercollegiate Guidelines Network (SIGN) method, which we modified placing more emphasis on expert opinion and consensus, whilst maintaining systematic rigour and transparency of processes. The development process includes: - Identification of key management issues by guideline group leaders. - Targeted, systematic literature searches using PubMed. - Review, identification and grading of results by panel of invited experts. - Consensus meetings at which experts present, discuss and agree recommendations. - Initial drafting of guideline document which is circulated amongst experts and stakeholders for comments. - Amendments incorporated and guidelines finalised. - Guidelines piloted and evaluated. - International dissemination. The process has involved 49 experts from 8 countries reviewing between them, over 1000 papers. The WS guidelines are currently being piloted in 20 centres, by paediatricians and geneticists. The first draft of AS guidelines has been circulated for feedback. Consensus meetings for NS and KS will be held very shortly. The finished guidelines will be available from the DYSCERNE website.