Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes.

BACKGROUND & AIMS: Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA. METHODS: We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models. RESULTS: A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA. CONCLUSIONS: BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes. IMPACT AND IMPLICATIONS: Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.

Genetic analysis for type 1 diabetes genes in juvenile dermatomyositis unveils genetic disease overlap.

OBJECTIVES: JDM is a serious autoimmune and complex genetic disease. Another autoimmune genetic disease, type 1 diabetes (T1D), has been observed for significantly increased prevalence in families with JDM, while increased JDM risk has also been observed in T1D cases. This study aimed to study whether these two autoimmune diseases, JDM and T1D, share common genetic susceptibility. METHODS: From 169 JDM families, 121 unrelated cases with European ancestry (EA) were identified by genome-wide genotyping, principal component analysis and identical-by-descent (IBD) analysis. T1D genetic risk score (GRS) were calculated in these cases and were compared with 361 EA T1D cases and 1943 non-diabetes EA controls. A total of 113 cases of the 121 unrelated European cases were sequenced by whole exome sequencing. RESULTS: We observed increased T1D GRS in JDM cases (P = 9.42E-05). Using whole exome sequencing, we uncovered the T1D genes, phospholipase B1, cystic fibrosis transmembrane conductance regulator, tyrosine hydroxylase, CD6 molecule, perforin 1 and dynein axonemal heavy chain 2, potentially associated with JDM by the burden test of rare functional coding variants. CONCLUSION: Novel mechanisms of JDM related to these T1D genes are suggested by this study, which may imply novel therapeutic targets for JDM and warrant further study.

Effect of micro-osteoperforations on the gene expression profile of the periodontal ligament of orthodontically moved human teeth.

OBJECTIVES: This study aimed to evaluate the effect of micro-osteoperforations (MOPs) on the gene expression profile of the periodontal ligament (PDL) of orthodontically moved teeth. MATERIALS AND METHODS: Fifteen participants were randomly assigned into two groups: tooth movement only (Tr1, n = 7) and tooth movement supplemented with MOPs (Tr2, n = 8). In each subject, orthodontic tooth movement (OTM) was performed on premolar in one side, while no force was applied on contralateral premolar (Unt, n = 15). Seven days after loading, premolars were extracted for orthodontic reasons. RNA extraction from PDL and subsequent RNA-sequencing were performed. False discovery rates (Padj < 0.05) and log2 fold change (+ / - 1.5) thresholds were used to identify sets of differentially expressed genes (DEGs) among the groups. DEGs were analyzed with gene ontology enrichment, KEGG, and network analysis. RESULTS: Three hundred thirty-one DEGs were found between Tr1 and Unt, and 356 between Tr2 and Unt. Although, there were no significantly DEGs between Tr2 and Tr1, DEGs identified exclusively in Tr1 vs. Unt were different from those identified exclusively in Tr2 vs. Unt. In Tr1, genes were related to bone metabolism processes, such as osteoclast and osteoblast differentiation. In Tr2, genes were associated to inflammation processes, like inflammatory and immune responses, and cellular response to tumor necrosis factor. CONCLUSIONS: MOPs do not significantly alter the PDL gene expression profile of orthodontically moved human teeth. This study provides for the first time evidence on the whole PDL gene expression profiles associated to OTM in humans. Novel biomarkers for OTM are suggested for additional research. Clinical relevance The identified biomarkers provide new insights into the molecular mechanisms that would occur when OTM is supplemented with MOPs. These markers are expected to be useful in the near future for the application of personalized strategies related to the OTM.

Are serum brain-derived neurotrophic factor concentrations related to brain structure and psychopathology in late childhood and early adolescence?

OBJECTIVE: Mental disorders can have a major impact on brain development. Peripheral blood concentrations of brain-derived neurotrophic factor (BDNF) are lower in adult psychiatric disorders. Serum BDNF concentrations and BDNF genotype have been associated with cortical maturation in children and adolescents. In 2 large independent samples, this study tests associations between serum BDNF concentrations, brain structure, and psychopathology, and the effects of BDNF genotype on BDNF serum concentrations in late childhood and early adolescence. METHODS: Children and adolescents (7-14 years old) from 2 cities (n = 267 in Porto Alegre; n = 273 in São Paulo) were evaluated as part of the Brazilian high-risk cohort (HRC) study. Serum BDNF concentrations were quantified by sandwich ELISA. Genotyping was conducted from blood or saliva samples using the SNParray Infinium HumanCore Array BeadChip. Subcortical volumes and cortical thickness were quantified using FreeSurfer. The Development and Well-Being Behavior Assessment was used to identify the presence of a psychiatric disorder. RESULTS: Serum BDNF concentrations were not associated with subcortical volumes or with cortical thickness. Serum BDNF concentration did not differ between participants with and without mental disorders, or between Val homozygotes and Met carriers. CONCLUSIONS: No evidence was found to support serum BDNF concentrations as a useful marker of developmental differences in brain and behavior in early life. Negative findings were replicated in 2 of the largest independent samples investigated to date.

Common variants at 5q33.1 predispose to migraine in African-American children.

BACKGROUND: Genome-wide association studies (GWASs) have identified multiple susceptibility loci for migraine in European adults. However, no large-scale genetic studies have been performed in children or African Americans with migraine. METHODS: We conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. We then attempted to replicate our primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects. RESULTS: The results of this study indicate that common variants at 5q33.1 associated with migraine risk in African-American children (rs72793414, p=1.94×10-9). The association was validated in an independent study (p=3.87×10-3) for an overall meta-analysis p value of 3.81×10-10. eQTL (Expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1. NMUR2 encodes a G protein-coupled receptor of neuromedin-U (NMU). NMU, a highly conserved neuropeptide, participates in diverse physiological processes of the central nervous system. CONCLUSIONS: This study provides new insights into the genetic basis of childhood migraine and allow for precision therapeutic development strategies targeting migraine patients of African-American ancestry.

Heterozygous Deletion Impacting SMARCAD1 in the Original Kindred with Absent Dermatoglyphs and Associated Features (Baird, 1964).

In 1964, Baird described a family with adermatoglyphia, facial milia, and skin fragility. Using whole exome sequencing, genotyping, and Sanger sequencing, we identified a 116-kb heterozygous deletion involving exons 1-9 of SMARCAD1 in descendants of this kindred. This contrasts with point mutations within exon 9 in all other reported families.

Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins.

Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.

Loss-of-Function Mutations in KIF15 Underlying a Braddock-Carey Genocopy.

Braddock-Carey Syndrome (BCS) is characterized by microcephaly, congenital thrombocytopenia, Pierre-Robin sequence (PRS), and agenesis of the corpus callosum. BCS has been shown to be caused by a 21q22.11 microdeletion that encompasses multiple genes. Here, we report a BCS genocopy characterized by congenital thrombocytopenia and PRS that is caused by a loss-of-function mutation in KIF15 in a consanguineous Saudi Arabian family. Mutations of mitotic kinesins are a well-established cause of microcephaly. To our knowledge, KIF15 is the first kinesin to be associated with congenital thrombocytopenia.

Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy.

Food allergy is a significant public health concern, especially among children. Previous candidate gene studies suggested a few susceptibility loci for food allergy, but no study investigated the contribution of copy number variations (CNVs) to food allergy on a genome-wide scale. To investigate the genetics of food allergy, we performed CNV assessment using high-resolution genome-wide single nucleotide polymorphism arrays. CNV calls from a total of 357 cases with confirmed food allergy and 3980 controls were analyzed within a discovery cohort, followed by a replication analysis composed of 167 cases and 1573 controls. We identified that CNVs in CTNNA3 were significantly associated with food allergy in both the discovery cohort and the replication cohort. Of particular interest, CTNNA3 CNVs hit exons or intron regions rich in histone marker H3K4Me1. CNVs in a second gene (RBFOX1) showed a significant association (p = 7.35 × 10(-5)) with food allergy at the genome-wide level in our meta-analysis of the European ancestry cohorts. The presence of these CNVs was confirmed by quantitative PCR. Furthermore, knockdown of CTNNA3 resulted in upregulation of CD63 and CD203c in mononuclear cells upon PMA stimulation, suggesting a role in sensitization to allergen. We uncovered at least two plausible genes harboring CNV loci that are enriched in pediatric patients with food allergies. The novel gene candidates discovered in this study by genome-wide CNV analysis are compelling drug and diagnostic targets for food allergy.

Copy number variation analysis reveals additional variants contributing to endometriosis development.

PURPOSE: Endometriosis is a gynecological disease influenced by multiple genetic and environmental factors. The aim of the current study was to use SNP-array technology to identify genomic aberrations that may possibly contribute to the development of endometriosis. METHODS: We performed an SNP-array genotyping of pooled DNA samples from both patients (n = 100) and controls (n = 50). Copy number variation (CNV) calling and association analyses were performed using PennCNV software. MLPA and TaqMan Copy-Number assays were used for validation of CNVs discovered. RESULTS: We detected 49 CNV loci that were present in patients with endometriosis and absent in the control group. After validation procedures, we confirmed six CNV loci in the subtelomeric regions, including 1p36.33, 16p13.3, 19p13.3, and 20p13, representing gains, while 17q25.3 and 20q13.33 showed losses. Among the intrachromosomal regions, our results revealed duplication at 19q13.1 within the FCGBP gene (p = 0.007). CONCLUSIONS: We identified CNVs previously associated with endometriosis, together with six suggestive novel loci possibly involved in this disease. The intergenic locus on chromosome 19q13.1 shows strong association with endometriosis and is under further functional investigation.

A current snapshot of common genomic variants contribution in psychiatric disorders.

In the past decade, numerous advances were achieved in psychiatric genetics. Particularly, the genome wide association studies (GWAS) have contributed to uncovering new genes and pathways associated to psychiatric disorders (PDs). At the same time, with increasing sample sizes in the GWAS, the polygenic risk score (PRS) promoted an additional tool for identification and evaluation the genetic risk quantitatively in PDs. This concept review presents the state of the art GWAS analysis and PRS focusing on the genetic underpinnings of PDs. © 2016 Wiley Periodicals, Inc.

Gene expression in B-1 cells from lupus-prone mice.

New Zealand Black X New Zealand White F1 [(NZB/NZW)F1] mice develop an autoimmune condition with similarities to human systemic lupus erythematosus (SLE). In this study, we demonstrate that B-1 cells, which have previously been reported to be involved in several autoimmune diseases, have altered gene expression in these mice. RNA was extracted from purified B-1 cells of disease-free C57BL/6 mice and lupus-prone (NZB/NZW)F1 mice. Gene expression was analysed using DNA microarray techniques and validated by real time reverse transcriptase polymerase chain reaction (RT-PCR). In (NZB/NZW)F1 mice, some genes had altered expression patterns compared to disease-free controls. Specifically, the upregulation of Ifitm1, Pvrl2 and Ifi202b and downregulation of Trp53bp1 mRNA were observed in (NZB/NZW)F1 mice. These genes are known to be associated with autoimmune diseases. This pattern of gene expression in B-1 cells could understanding of the pathogenesis of SLE. Thus, it is reasonable to hypothesise that the altered gene expression observed in B-1 cells in our experimental model is important for SLE prognosis and therapy, and these implications are discussed herein.

Sleep is not just for the brain: transcriptional responses to sleep in peripheral tissues.

BACKGROUND: Many have assumed that the primary function of sleep is for the brain. We evaluated the molecular consequences of sleep and sleep deprivation outside the brain, in heart and lung. Using microarrays we compared gene expression in tissue from sleeping and sleep deprived mice euthanized at the same diurnal times. RESULTS: In each tissue, nearly two thousand genes demonstrated statistically significant differential expression as a function of sleep/wake behavioral state. To mitigate the influence of an artificial deprivation protocol, we identified a subset of these transcripts as specifically sleep-enhanced or sleep-repressed by requiring that their expression also change over the course of unperturbed sleep. 3% and 6% of the assayed transcripts showed "sleep specific" changes in the lung and heart respectively. Sleep specific transcripts in these tissues demonstrated highly significant overlap and shared temporal dynamics. Markers of cellular stress and the unfolded protein response were reduced during sleep in both tissues. These results mirror previous findings in brain. Sleep-enhanced pathways reflected the unique metabolic functions of each tissue. Transcripts related to carbohydrate and sulfur metabolic processes were enhanced by sleep in the lung, and collectively favor buffering from oxidative stress. DNA repair and protein metabolism annotations were significantly enriched among the sleep-enhanced transcripts in the heart. Our results also suggest that sleep may provide a Zeitgeber, or synchronizing cue, in the lung as a large cluster of transcripts demonstrated systematic changes in inter-animal variability as a function of both sleep duration and circadian time. CONCLUSION: Our data support the notion that the molecular consequences of sleep/wake behavioral state extend beyond the brain to include peripheral tissues. Sleep state induces a highly overlapping response in both heart and lung. We conclude that sleep enhances organ specific molecular functions and that it has a ubiquitous role in reducing cellular metabolic stress in both brain and peripheral tissues. Finally, our data suggest a novel role for sleep in synchronizing transcription in peripheral tissues.

Alterations in microRNA of extracellular vesicles associated with major depression, attention-deficit/hyperactivity and anxiety disorders in adolescents.

Extracellular vesicles (EVs) are present in numerous peripheral bodily fluids and function in critical biological processes, including cell-to-cell communication. Most relevant to the present study, EVs contain microRNAs (miRNAs), and initial evidence from the field indicates that miRNAs detected in circulating EVs have been previously associated with mental health disorders. Here, we conducted an exploratory longitudinal and cross-sectional analysis of miRNA expression in serum EVs from adolescent participants. We analyzed data from a larger ongoing cohort study, evaluating 116 adolescent participants at two time points (wave 1 and wave 2) separated by three years. Two separate data analyses were employed: A cross-sectional analysis compared individuals diagnosed with Major Depressive Disorder (MDD), Anxiety disorders (ANX) and Attention deficit/Hyperactivity disorder (ADHD) with individuals without psychiatric diagnosis at each time point. A longitudinal analysis assessed changes in miRNA expression over time between four groups showing different diagnostic trajectories (persistent diagnosis, first incidence, remitted and typically developing/control). Total EVs were isolated, characterized by size distribution and membrane proteins, and miRNAs were isolated and sequenced. We then selected differentially expressed miRNAs for target prediction and pathway enrichment analysis. In the longitudinal analysis, we did not observe any statistically significant results. In the cross-sectional analysis: in the ADHD group, we observed an upregulation of miR-328-3p at wave 1 only; in the MDD group, we observed a downregulation of miR-4433b-5p, miR-584-5p, miR-625-3p, miR-432-5p and miR-409-3p at wave 2 only; and in the ANX group, we observed a downregulation of miR-432-5p, miR-151a-5p and miR-584-5p in ANX cases at wave 2 only. Our results identified previously observed and novel differentially expressed miRNAs and their relationship with three mental health disorders. These data are consistent with the notion that these miRNAs might regulate the expression of genes associated with these traits in genome-wide association studies. The findings support the promise of continued identification of miRNAs contained within peripheral EVs as biomarkers for mental health disorders.

Autistic disorder phenotype associated to a complex 15q intrachromosomal rearrangement.

The proximal regions of acrocentric chromosomes, particularly 15q11.2, are frequently involved in structural rearrangement. However, interstitial duplications involving one of the chromosome 15 homologues are less frequent, with few patients described with molecular techniques. These patients present distinctive clinical findings including developmental delay and intellectual disability, minor dysmorphic facial features, epilepsy, and autistic behavior. Here we describe an interstitial rearrangement of chromosome 15 composed of a triplication -6.9 Mb from 15q11.2 to 15q13.2 followed by a duplication of -2.4 Mb from 15q13.2 to 15q13.3, defined using different approaches as MLPA, qPCR, array and FISH. FISH revealed that the middle part of the triplicated segment was in inverted position. The parental origin of the rearrangement was assessed using methylation assay and SNP array that revealed the maternal origin of the additional material. The patient presents most of the clinical features associated to 15q11.2 triplication: minor dysmorphic facial features, generalized epilepsy, absence seizures, intellectual disability, and autistic behavior. In conclusion, the use of more accurate molecular tools enabled a detailed investigation, providing the identification of intrachromosome duplication/triplication and bringing new light to the study of genetic causes of autistic disorders.

Association of Inherited Copy Number Variation in ADAM3A and ADAM5 Pseudogenes with Oropharynx Cancer Risk and Outcome.

Inherited copy number variations (CNVs) can provide valuable information for cancer susceptibility and prognosis. However, their association with oropharynx squamous cell carcinoma (OPSCC) is still poorly studied. Using microarrays analysis, we identified three inherited CNVs associated with OPSCC risk, of which one was validated in 152 OPSCC patients and 155 controls and related to pseudogene-microRNA-mRNA interaction. Individuals with three or more copies of ADAM3A and ADAM5 pseudogenes (8p11.22 chromosome region) were under 6.49-fold increased risk of OPSCC. ADAM5 shared a highly homologous sequence with the ADAM9 3'-UTR, predicted to be a binding site for miR-122b-5p. Individuals carrying more than three copies of ADAM3A and ADAM5 presented higher ADAM9 expression levels. Moreover, patients with total deletion or one copy of pseudogenes and with higher expression of miR-122b-5p presented worse prognoses. Our data suggest, for the first time, that ADAM3A and ADAM5 pseudogene-inherited CNV could modulate OPSCC occurrence and prognosis, possibly through the interaction of ADAM5 pseudogene transcript, miR-122b-5p, and ADAM9.

Mechanisms of ring chromosome formation, ring instability and clinical consequences.

BACKGROUND: The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients. METHODS: Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent in situ Hybridization). RESULTS: The ring chromosomes of patients I to XIV were determined to be, respectively: r(3)(p26.1q29), r(4)(p16.3q35.2), r(10)(p15.3q26.2), r(10)(p15.3q26.13), r(13)(p13q31.1), r(13)(p13q34), r(14)(p13q32.33), r(15)(p13q26.2), r(18)(p11.32q22.2), r(18)(p11.32q21.33), r(18)(p11.21q23), r(22)(p13q13.33), r(22)(p13q13.2), and r(22)(p13q13.2). These rings were found to have been formed by different mechanisms, such as: breaks in both chromosome arms followed by end-to-end reunion (patients IV, VIII, IX, XI, XIII and XIV); a break in one chromosome arm followed by fusion with the subtelomeric region of the other (patients I and II); a break in one chromosome arm followed by fusion with the opposite telomeric region (patients III and X); fusion of two subtelomeric regions (patient VII); and telomere-telomere fusion (patient XII). Thus, the r(14) and one r(22) can be considered complete rings, since there was no loss of relevant genetic material. Two patients (V and VI) with r(13) showed duplication along with terminal deletion of 13q, one of them proved to be inverted, a mechanism known as inv-dup-del. Ring instability was detected by ring loss and secondary aberrations in all but three patients, who presented stable ring chromosomes (II, XIII and XIV). CONCLUSIONS: We concluded that the clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability. Epigenetic factors due to the circular architecture of ring chromosomes must also be considered, since even complete ring chromosomes can result in phenotypic alterations, as observed in our patients with complete r(14) and r(22).

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70-80%) or hereditary (20-30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

Trisomy 16q21 --> qter: Seven-year follow-up of a girl with unusually long survival.

The 16q21 --> qter duplication is a chromosomal abnormality rarely found in liveborn infants, with only four published cases. We report here on the 7-year follow-up of a female patient with trisomy 16q21 --> qter due to a maternal balanced translocation t(4;16)(q35.2;q21). The patient shows severe mental retardation, congenital heart malformations, nephropathy, and other congenital anomalies. The derivative chromosome was characterized by GTG banding, fluorescent in situ hybridization (FISH) with different BAC probes and the array technique, in order to map the breakpoints. The patient has a 16q21 --> qter duplication, with a 4q35 --> qter monosomy, which we assume does not contribute to the abnormal phenotype. This is the first reported case of postnatal survival to the age of 7 years, an unusually long time in this chromosomal syndrome.

Cytogenetic and molecular evaluation and 20-year follow-up of a patient with ring chromosome 14.

We present a 20-year follow-up on a patient with a ring chromosome 14. The ring chromosome was studied by fluorescence in-situ hybridization (FISH), multiplex-ligation probe amplification (MLPA), and genome wide SNP array, and no deletions of chromosome 14 were detected, although the telomeric repeat sequence was absent from the ring chromosome. The patient had skeletal abnormalities, and susceptibility to infections, as well as seizures and retinal pigmentation, which are commonly found in individuals with a ring 14. Our patient corroborates the idea that even when no genes are lost during ring formation, a complete ring chromosome can produce phenotypic alterations, which presumably result from ring instability or gene silencing due to the new chromosomal architecture.