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We report linkage analysis in a new family with nonspecific X-linked mental retardation, using 27 polymorphic markers covering the entire X-chromosome. We could assign the underlying disease gene, denoted MRX65, to the pericentromeric region, with flanking markers DXS573 in Xp11.3 and DXS990 in Xq21.33. A maximum LOD score of 3.64 was found at markers ALAS2 (Xp11.22) and DXS453 (Xq12) at straight theta = 0. Twenty-five of the 58 reported MRX families are linked to a region that is partially overlapping with the region reported here. Extension of the pedigree showed a number of unaffected distant relatives with haplotypes corresponding to the disease locus. Apparently, a new mutation in a female is causative for the disease in the family reported here. Furthermore, we show the importance of combining clinical, cytogenetic, and molecular studies since one of the family members, expected to be affected by the same genetic defect, has a 48,XXXY karyotype.

Four families are described in which mental retardation segregates in an X-linked fashion. Mental retardation was the only consistent clinical finding in all affected males. The degree of retardation varied from mild to profound both between and within families. Linkage analysis localized the genetic defect of MRX43 to Xp22. 31-p21.2, MRX44 to Xp11.3-p11.21, MRX45 to Xp11.3-p11.21, and MRX52 to Xp11.21-q21.33 with LOD scores of >2 at straight theta = 0.0 in all four families.

SummaryHypomagnesemia due to isolated renal magnesium loss has previously been demonstrated in two presumably unrelated Dutch families with autosomal dominant mode of inheritance. Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic. In a genomewide linkage study, we first excluded a possible candidate region, on chromosome 9q, that encompasses the gene for intestinal hypomagnesemia with secondary hypocalcemia and, subsequently, found linkage to markers on chromosome 11q23. Detailed haplotype analyses identified a common haplotype segregating in both families, suggesting both their relationship through a common ancestor and the existence of a single, hypomagnesemia-causing mutation within them. The maximum two-point LOD score (Zmax) was found for marker D11S4127 (Zmax=6.41 at a recombination fraction of .00), whereas a multipoint analysis gave a Zmax of 8.24 between markers D11S4142 and D11S4171. Key recombination events define a 5.6-cM region between these two markers on chromosome 11q23. We conclude that this region encompasses a gene, involved in renal magnesium handling, that is mutated in our patients and is different from the gene involved in intestinal magnesium handling.

A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks’ gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (−3 SDS) and head circumference 52.5 cm (⩽2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes …

The regulation of water excretion by the kidney is one of the few physiologic processes that are prominent in everyday life. This process predominantly occurs in renal collecting duct cells, where transcellular water reabsorption is induced after binding of the pituitary hormone arginine-vasopressin to its vasopressin type-2 receptor and the subsequent insertion of aquaporin-2 (AQP2) water channels in the apical membrane of these cells. Removal of the hormone triggers endocytosis of AQP2 and restores the water-impermeable state of the collecting duct cells. Nephrogenic diabetes insipidus is characterized by the inability of the kidney to concentrate urine in response to vasopressin; the vasopressin type-2 receptor and the AQP2 water channel have both been shown to be involved in this disease. This article focuses on mutations in the vasopressin V2 receptor and aquaporin-2 water channel identified in nephrogenic diabetes insipidus patients, and on the effects of these mutations on the transport and function of these proteins upon expression in cell systems.

In the past year, significant progress has been achieved in the research on aquaporins (AQPs), a family of structurally related molecular water channels. Three novel AQPs were identified, giving a total of ten mammalian AQPs. An important step forward in identifying the aqueous pore in AQP molecules was the determination of the three-dimensional structure of AQP1. The expression pattern of individual AQPs in different tissues was determined in more detail and AQP-knockout mice have been generated. The discovery of a severe urinary concentrating defect in AQP1-knockout mice was remarkable. Only AQP2, the vasopressin-sensitive water channel in the kidney, which is mutated in autosomal recessive and dominant cases of nephrogenic diabetes insipidus, has been shown to be involved in human disease. The finding of changed AQP2 expression in several acquired water balance disorders may pave the way toward developing treatments for these clinical problems.

Aquaporins are integral membrane proteins, which function as specialized water channels to facilitate the passage of water through the cell membrane. In mammals six different aquaporins have been identified up to now, four of which (aquaporin-1 to aquaporin-4) are expressed in the kidney. Because of its importance for normal water homeostasis and its involvement in many water balance disorders, aquaporin-2, the predominant vasopressin-regulated water channel of the renal collecting duct, is discussed in detail.

Parkinson's disease (PD) is a multifactorial disorder, caused by a combination of age, genetics and environmental factors. Nigral cells are susceptible to multiple causes of derangement of normal cell function, all of which may contribute to the same Parkinson phenotype. Autosomal dominant alpha-synuclein-gene PD represents one of the pure genetic forms, whereas cases of sporadic PD probably depend more on age and environmental factors, MPTP-Parkinsonism being the purest example of an environmentally caused Parkinson phenotype. This review suggests that pesticides-herbicides, smoking and head trauma probably represent the most eligible candidates for environmental factors involved in provoking PD or influencing its natural course.

Vasopressin V2 receptors, expressed from an x-chromosomal gene, are involved in antidiuresis, but also in release of coagulation factor VIII and von Willebrand factor (vWF). The present study describes autosomal recessive nephrogenic diabetes insipidus (NDI) in a large cluster of patients in Israel's Lower-Galilee. Evidence for an intact V2 receptor was concluded by their normal increase in factor VIII and vWF after desmopressin infusion. Thus, in these patients a defect in the pathway beyond the V2 receptor was suspected. The recent cloning of the human Aquaporin-2 gene enabled us to test this gene as a candidate for such a postreceptor defect. Direct sequencing of the Aquaporin-2 gene revealed a G298T substitution causing a Gly100Stop nonsense mutation in the third transmembrane region. Because this putative disease-causing mutation was identified in index patients of different families, we suggest that all patients are descendants of a common ancestor. Thus, this new entity is characterized by an autosomal recessive NDI. The differential response of clotting factors and urine osmolality to desmopressin may provide a simple tool for clinical diagnosis of a V2-postreceptor defect. The early stop-codon of Aquaporin-2 results in complete resistance to vasopressin antidiuretic effect.

Nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine in response to vasopressin. The autosomal recessive form of NDI is caused by mutations in the AQP2 gene, encoding the vasopressin-regulated water channel of the kidney collecting duct. This report presents three new mutations in the AQP2 gene that cause NDI, resulting in A147T-, T126M-, or N68S-substituted AQP2 proteins. Expression of the A147T and T126M mutant AQP2 proteins in Xenopus oocytes revealed a relatively small, but significant increase in water permeability, whereas the water permeability of N68S expressing oocytes was not increased. cRNA encoding missense and wild-type AQP2 were equally stable in oocytes. Immunoblots of oocyte lysates showed that only the A147T mutant protein was less stable than wild-type AQP2. The mutant AQP2 proteins showed, in addition to the wild-type 29-kd band, an endoplasmic reticulum-retarded form of AQP2 of approximately 32 kd. Immunoblotting and immunocytochemistry demonstrated only intense labeling of the plasma membranes of oocytes expressing wild-type AQP2. In summary, two mutant AQP2 proteins encoded in NDI are functional water channels. Therefore, the major cause underlying autosomal recessive NDI is the misrouting of AQP2 mutant proteins.

Partial iris hypoplasia in a patient with an interstitial subtelomeric 6p deletion not including the forkhead transcription factor gene FOXC1

Background Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. Conclusions This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Objective This study aims to analyze differences in characteristics between women who opted for invasive testing after first-trimester combined testing and those who did not. Method Follow-up was performed in 20 215 combined tests conducted between 2007 and 2011 in the central region of the Netherlands. Multivariate logistic regression analysis compared variables (Down syndrome risk estimate, maternal age, previous Down syndrome pregnancy, IVF/ICSI, parity and nuchal translucency measurement) between different groups. Results 65.4% of women with a Down syndrome risk estimate ≥1 in 200 opted for invasive 49 testing. In a multivariate model, women opting for invasive testing were significantly younger (odds ratio 0.92; 95% confidence interval 0.88–0.95) and less likely to have had IVF/ICSI (odds ratio 0.57; 95% confidence interval 0.37–0.87) than women opting out on invasive testing. In this high risk group, women

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The various phenotypes of hypospadias may result from disturbances of dissimilar embryonic processes in different time windows, suggesting aetiological heterogeneity; however, only a few studies have investigated the risk factors for the different hypospadias phenotypes. The study confirmed that genetic predisposition possibly plays a role in anterior and middle hypospadias, as shown by the large effect estimates for familial occurrence of these forms of hypospadias. By contrast, the posterior phenotype was more often associated with pregnancy-related factors, such as primiparity, preterm delivery, and being small for gestational age. New findings were that hormone-containing contraceptive use after conception increased the risk of middle and posterior hypospadias, while multiple pregnancies were associated with the posterior form in particular.To identify specific risk factors for different phenotypes of hypospadias that may arise as a result of dissimilar embryonic processes in different time windows.A total of 405 hypospadias cases and 627 male controls were included in a Dutch case-control study. Medical records of cases were reviewed to determine the anatomical location of the urethral opening, while demographic, lifestyle and pregnancy-related risk factor data were obtained from self-administered questionnaires. Multivariable and multinomial logistic regression analyses were used to calculate effect estimates for the group containing all cases of hypospadias and for the different hypospadias phenotypes.Cases were subdivided into anterior (glandular and coronal; 59%), middle (penile; 29%) and posterior (penoscrotal, scrotal and perineal; 12%) hypospadias. Being a twin/triplet, primiparity, preterm delivery, and being small for gestational age were associated with hypospadias, particularly in posterior cases. Family history of hypospadias increased the risk of hypospadias, an effect that seemed to be more predominant in anterior and middle forms. Maternal obesity seemed to increase the risk of hypospadias in general, and hormone-containing contraceptive use during pregnancy especially increased the risk of middle and posterior hypospadias.Our study provides some indications for aetiological heterogeneity of hypospadias, separating anterior and middle phenotypes from posterior hypospadias. Future research should continue to try to establish which specific risk factors and mechanisms may differ according to hypospadias phenotype.

Gitelman syndrome is a mostly autosomal recessive disorder affecting the renal tubular function associated with hypokalemia and hypomagnesemia. Functional studies point to a defect in the distal renal tubule in the thiazide-sensitive, electroneutral sodium-chloride co-transporter (TSC). Based upon the localization of a 2.6 cDNA encoding the human TSC to chromosome 16q13, polymorphic markers spanning the region from 16p12 to 16q21 were tested for linkage to the Gitelman syndrome locus in three Dutch families with autosomal recessive inheritance of this disorder. Using two-point linkage analysis, a maximum LOD score (Zmax of 4.49 (at theta = 0.00) was found for the marker D16S408. One crucial recombination event places the Gitelman syndrome locus distal to D16S419 at 16q12-13. Subsequently we have tested our group of Gitelman patients for mutations in the human TSC gene. Two mutations were identified in three Gitelman families. Our study confirms that the human TSC gene is involved in Gitelman syndrome. Patients from three Gitelman families reveal two identical human TSC mutations, suggesting these families share a common ancestor.

Contains fulltext : 107969.pdf (Publisher’s version ) (Open Access) Integrins are transmembrane alphabeta glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin alpha3beta1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, alpha3beta1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin alpha3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the alpha3 precursor prevented its heterodimerization with beta1, whereas CD151 association with the alpha3 subunit occurred normally. Consequently, the beta1 precursor accumulated in the ER, and the mutant alpha3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional alpha3beta1, causing a fatal multiorgan disorder.

Item does not contain fulltext Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth. (c) 2012 Wiley Periodicals, Inc.

Contains fulltext : 170812.pdf (Publisher’s version ) (Closed access) BACKGROUND: Our clinical observations and two earlier studies indicate familial clustering to be involved in chronic chilblains. Demonstrating phenotypic familial aggregation is a next step to investigate the origin of familial clustering. OBJECTIVE: This study was initiated to assess evidence for phenotypic familial aggregation in chronic chilblains. METHODS: Using a case-control family design in a primary care setting, we computed the familial relative risk of at least one episode of chronic chilblains during life with 95% confidence intervals (CIs). The study population consisted of 192 relatives of 31 case probands (at least one confirmed episode of chronic chilblains). The control population consisted of 178 relatives of 31 sex- and age-matched index controls (no history of chronic chilblains). RESULTS: The familial relative risk of chronic chilblains was 3.6 (95% CI 1.9-7.3). Additional sensitivity analysis shows similar figures. CONCLUSION: We demonstrate robust phenotypic familial aggregation in chronic chilblains.

Contains fulltext : 168068.pdf (Publisher’s version ) (Closed access) The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5-15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.

Background: Vitamin B6 is present in various forms (vitamers) in the diet that need to be metabolized to pyridoxal phosphate (PLP), the active cofactor form of vitamin B6. In literature, the liver has been reported to be the major site for this conversion, whereas the exact role of the intestine remains to be elucidated.Objective: To gain insight into the role of the intestine in human vitamin B6 metabolism.Materials and Methods: Expression of the enzymes pyridoxal kinase (PK), pyridox(am)ine phosphate oxidase (PNPO) and PLP-phosphatase was determined in Caco-2 cells and in lysates of human intestine. Vitamin B6 uptake, conversion and excretion were studied in polarized Caco-2 cell monolayers. B6 vitamer concentrations (pyridoxine (PN), pyridoxal (PL), PLP, pyridoxamine (PM), pyridoxamine phosphate (PMP)) and pyridoxic acid (PA) were quantified by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) using stable isotope-labeled internal standards.Results: The enzymatic system involved in vitamin B6 metabolism (PK, PNPO and PLP-phosphatase) is fully expressed in Caco-2 cells as well as in human intestine. We show uptake of PN, PM and PL by Caco-2 cells, conversion of PN and PM into PL and excretion of all three unphosphorylated B6 vitamers.Conclusion: We demonstrate, in a Caco-2 cell model, that the intestine plays a substantial role in human vitamin B6 metabolism.

Contains fulltext : 108864.pdf (Publisher’s version ) (Closed access) Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis in conjunction with significant hypomagnesemia and hypocalciuria. The GS phenotype is caused by mutations in the solute carrier family 12, member 3 (SLC12A3) gene that encodes the thiazide-sensitive NaCl cotransporter (NCC). We analyzed DNA samples of 163 patients with a clinical suspicion of GS by direct sequencing of all 26 exons of the SLC12A3 gene. In total, 114 different mutations were identified, 31 of which have not been reported before. These novel variants include 3 deletions, 18 missense, 6 splice site and 4 nonsense mutations. We selected seven missense mutations to investigate their effect on NCC activity and plasma membrane localization by using the Xenopus laevis oocyte expression system. The Thr392Ile mutant did not display transport activity (probably class 2 mutation), while the Asn442Ser and Gln1030Arg NCC mutants showed decreased plasma membrane localization and consequently function, likely due to impaired trafficking (class 3 mutation). Even though the NaCl uptake was hampered for NCC mutants Glu121Asp, Pro751Leu, Ser475Cys and Tyr489His, the transporters reached the plasma membrane (class 4 mutation), suggesting an effect on NCC regulation or ion affinity. The present study shows the identification of 38 novel mutations in the SLC12A3 gene and provides insight into the mechanisms that regulate NCC.

Contains fulltext : 107835.pdf (Author’s version preprint ) (Open Access) PURPOSE: Hypospadias is a common congenital malformation of the male external genitalia. Association studies for single nucleotide polymorphisms in genes encoding steroid 5alpha-reductase, estrogen receptors 1 and 2, and activating transcription factor 3 have been equivocal. We examined whether nonreplication of findings for 4 single nucleotide polymorphisms in these genes could be due to interaction with environmental exposures. MATERIALS AND METHODS: We genotyped 712 Dutch hypospadias case-parent triads for the 4 single nucleotide polymorphisms, used questionnaire information to determine exposures and performed association tests using the log-linear approach. We studied gene-environment interactions for the 4 single nucleotide polymorphisms with exposure to estrogens, cytokines or cigarette smoke, multiple birth, being born small for gestational age, maternal hypertension or preeclampsia, high body mass index or primiparity. In addition, the presence of maternal genetic and parent of origin effects was tested. RESULTS: Gene-environment interactions were identified for rs523349 in SRD5A2 with estrogen exposure and maternal hypertension or preeclampsia, as well as for rs11119982 in ATF3 with exposure to cytokines. Both single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases. For rs6932902 in ESR1 only maternally derived alleles appeared to increase hypospadias risk in offspring. CONCLUSIONS: Interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.

BACKGROUND: We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype.METHODS AND RESULTS: We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated.CONCLUSIONS: HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.

Contains fulltext : 95685.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features. OBJECTIVE: To identify an additional causative gene in Sensenbrenner syndrome. METHODS: Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport. RESULTS: Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit. CONCLUSIONS: The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport.

Knoers, Nine Vam Devuyst, Olivier Kamsteeg, Erik-Jan Research Support, Non-U.S. Gov't England Eur J Hum Genet. 2011 Aug;19(8). doi: 10.1038/ejhg.2011.14. Epub 2011 Feb 23.

Contains fulltext : 107989.pdf (Publisher’s version ) (Open Access) Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p

Item does not contain fulltext Congenital anomalies of the kidney and urinary tract (CAKUT) are the commonest cause of chronic kidney disease in children. Structural anomalies within the CAKUT spectrum include renal agenesis, kidney hypo-/dysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. While most CAKUT cases are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. Animal experiments demonstrate that alterations in genes crucial for kidney development can cause experimental CAKUT, while expression studies implicate mislocalization and/or aberrant levels of the encoded proteins in human CAKUT. Further insight into the pathogenesis of CAKUT will improve strategies for early diagnosis, follow-up and treatment. Here, we outline a collaborative approach to identify and characterize novel factors underlying human CAKUT. This European consortium will share the largest collection of CAKUT patients available worldwide and undertake multidisciplinary research into molecular and genetic pathogenesis, with extension into translational studies to improve long-term patient outcomes.

Item does not contain fulltext Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg(2+) (re)absorption, particularly the luminal uptake of Mg(2+) along the nephron, has benefitted from positional cloning approaches in families with Mg(2+) reabsorption disorders; however, basolateral Mg(2+) transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg(2+) handling in patients of two unrelated families with unexplained dominant hypomagnesemia. In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg(2+) reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg(2+)-sensitive Na(+) currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg(2+) concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg(2+) concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg(2+), and its basolateral localization signify a critical role for CNNM2 in epithelial Mg(2+) transport.

Item does not contain fulltext The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Contains fulltext : 88378.pdf (author's version ) (Open Access) BACKGROUND: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form. OBJECTIVE: To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4). METHODS: SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed. RESULTS: 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype. CONCLUSIONS: Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed. 01 oktober 2010

Contains fulltext : 95737.pdf (Publisher’s version ) (Closed access) Contains fulltext : 95737a.pdf (Author’s version postprint ) (Open Access) Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase kappa, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 x 10(1)(1) and OR = 2.3, P = 2.9 x 10, respectively) and in the Dutch (OR = 3.9, P = 2.4 x 10 and OR = 3.8, P = 3.4 x 10) and Swedish (OR = 2.5, P = 2.6 x 10 and OR = 2.2, P = 2.7 x 10) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias.

Recent findings by Verdonk et al. show that the prevalence of work-related fatigue among 47,000 Dutch employees is greatest in highly-educated women, aged 50-64 years. Although the study has several limitations, the findings are alarming, demand urgent measures and should be on the shortlist of policy makers, employers, and company doctors. Reduced time pressure and emotional demand at work, adequate support for women's ambitions, and proper consideration for the work-private life balance are needed. Coaching may help women to become more assertive and generate more job control. In addition, the problem of workplace violence must be adequately addressed. I am of the strong opinion that work-related fatigue in women would significantly decrease if women were to occupy more leadership positions and top jobs. In such positions they would have greater autonomy and more opportunities to organise their work according to their own time schedules and insights. The time is ripe for women to be given a quota of top positions in the Netherlands.

Purpose Hypospadias is a common congenital malformation of the male external genitalia with a multifactorial etiology. Little is known about the genes involved in Hypospadias. A few genetic associations have been reported, but mainly in studies of small sample size. Most of these associations have not been replicated. The aim of this study was to investigate whether previously reported associations for four single nucleotide polymorphisms (SNPs) in genes involved in hormonal pathways could be replicated in a large Dutch Hypospadias sample. The SNPs investigated are rs523349 in steroid-5-alpha-reductase (SRD5A2), rs6932902 in estrogen receptor 1 (ESR1), rs2987983 in ESR2 and rs11119982 in activating transcription factor 3 (ATF3). Material and Methods We genotyped 620 Caucasian Hypospadias cases and 596 controls for the four SNPs using TaqMan-based genotyping. Results We did not replicate the associations of the SNPs in SRD5A2 and ESR1 with Hypospadias. The SNPs in ESR2 and ATF3 were borderline associated with Hypospadias (odds ratios 0.9 (95% confidence interval (CI) 0.7-1.0) and 1.2 (95% CI 1.0-1.4), respectively), but in the opposite direction compared to earlier publications. Stratification according to the localization of the urethral opening produced comparable results in the subgroups. Conclusions The lack of consistency between our and previously performed studies might represent spurious results or chance findings found in our or the earlier studies, differences in criteria used to select the study populations, or a real difference between the populations. These results once again confirm the importance of replication in genetic association approaches.

Massively parallel sequencing has tremendous diagnostic potential but requires enriched templates for sequencing. Here we report the validation of an arraybased sequence capture method in genetically heterogeneous disorders. The model disorder selected was AR ataxia, using five subjects with known mutations and two unaffected controls. The genomic sequences of seven disease genes, together with two control loci were targeted on a 2-Mb sequence-capture array. After enrichment, the patients' DNA samples were analyzed using one-quarter Roche GS FLX Titanium sequencing run, resulting in an average of 65Mb of sequence data per patient. This was sufficient for an average 25-fold coverage/base in all targeted regions. Enrichment showed high specificity; on average, 80% of uniquely mapped reads were on target. Importantly, this approach enabled automated detection of deletions and hetero- and homozygous point mutations for 6/7 mutant alleles, and greater than 99% accuracy for known SNP variants. Our results also clearly show reduced coverage for sequences in repeat-rich regions, which significantly impacts the reliable detection of genomic variants. Based on these findings we recommend a minimal coverage of 15-fold for diagnostic implementation of this technology. We conclude that massive parallel sequencing of enriched samples enables personalized diagnosis of heterogeneous genetic disorders and qualifies for rapid diagnostic implementation. Refereed/Peer-reviewed

Contains fulltext : 87531.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anorectal malformations (ARM) are major congenital malformations that usually require a multitude of surgical procedures at a very early age and have a large impact on the lives of patients and their parents. The causes of ARM are still largely unknown, but they are assumed to have a multifactorial etiology. A few studies focused on environmental risk factors, but evidence is still scarce. METHODS: In this Dutch case-control study (1996-2008), we investigated the role of maternal and paternal risk factors in the etiology of ARM. Parents of 85 ARM cases and 650 controls filled in a questionnaire. Controls were children treated with ear ventilation tubes. RESULTS: A higher occurrence of fever during the first trimester of pregnancy was found for case mothers compared to control mothers (odds ratio [OR], 5.1; 95% Confidence Interval [CI], 0.9, 28.1). Maternal occupational exposure to industrial cleaning agents and solvents increased the risk of ARM three times (OR, 2.9; 95% CI, 0.9, 9.3). Overweight (Body Mass Index [BMI] > or = 25 kg/m(2)) before pregnancy also seemed to be associated with ARM (OR, 1.8; 95% CI, 1.1, 2.8), as well as maternal multivitamin use during pregnancy (OR, 1.6; 95% CI, 1.0, 2.7), paternal smoking (OR, 1.8; 95% CI, 1.1, 2.9), and paternal occupational exposure to exhaust fumes (OR, 1.9; 95% CI, 1.0, 3.6). Reported ARM in at least one first- or second-degree family member greatly increased the risk of having a child with an ARM (OR, 40.3; 95% CI, 4.8, 342.8). CONCLUSIONS: This study revealed potential risk factors for ARM, including fever during pregnancy, maternal overweight, use of multivitamins, paternal smoking, and occupational exposures, but a familial component seems important as well. 01 maart 2010

Contains fulltext : 89406.pdf (Publisher’s version ) (Closed access) PURPOSE: The recently established International Consortium on Anorectal Malformations aims to identify genetic and environmental risk factors in the etiology of syndromic and nonsyndromic anorectal malformations (ARM) by promoting collaboration through data sharing and combined research activities. METHODS: The consortium attempts to recruit at least 1,000 ARM cases. DNA samples are collected from case-parent triads to identify genetic factors involved in ARM. Several genetic techniques will be applied, including SNP arrays, gene and whole exome sequencing, and a genome-wide association study. Questionnaires inquiring about circumstances before and during pregnancy will be used to obtain environmental risk factor data. RESULTS: Currently, 701 ARM cases have been recruited throughout Europe. Clinical data are available from all cases, and DNA samples and questionnaire data mainly from the Dutch and German cases. Preliminary analyses on environmental risk factors in the Dutch and German cohort found associations between ARM and family history of ARM, fever during first trimester of pregnancy and maternal job exposure to cleaning agents and solvents. CONCLUSION: First results show that both genetic and environmental factors may contribute to the multifactorial etiology of ARM. The International Consortium on Anorectal Malformations will provide possibilities to study and detect important genes and environmental risk factors for ARM, ultimately resulting in better genetic counseling, improved therapies, and primary prevention. 01 november 2010

Item does not contain fulltext With the completion of the Human Genome Project and the associated advances in genomic technologies, clinicians have at their disposal an increasing repertoire of tools to provide accurate and efficient diagnosis, assess disease predisposition and risk factors, and personalize therapeutic management. To date, more than 2,000 human disease genes have been identified, including genes involved in single-gene disorders that disrupt the structure and/or function of the kidney and developing urinary tract. The use of genetic tests for diagnostic purposes increasingly is being integrated into general medical practice and therefore it is important for clinicians to be familiar with the technical approaches and ethical implications of these methods. Here, we provide an overview of the utility and limitations of current genetic tests for diagnosis, prenatal examination, carrier detection, and presymptomatic testing of hereditary disorders, with emphasis on pediatric renal disorders. In addition, we describe new technical advances that are expected to be introduced into clinical practice in the coming years.

Publisher Summary Researchers have been shifting the focus of genetic testing from Mendelian disorders towards identifying susceptibility alleles that predispose individuals to developing complex traits, such as diabetic nephropathy, and incorporating pharmacogenomic testing to predict drug-genome interactions. Genetic testing involves the analysis of chromosomes, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or specific metabolites in order to detect variants that are associated with human disease or a pharmacological response. Direct testing refers to gene-specific evaluation of a DNA and/or RNA sample. The linkage-based testing is an indirect method that examines the segregation of genetic markers located near or within the disease-causing gene with disease phenotypes within a family. Genetic testing increasingly holds the potential to inform clinical practice and impact the outcomes of patients with the disorders that disrupt the structure, function, and/or developmental patterning of the glomerulus, tubules, and urogenital tract, and those that predispose to renal cell tumors. One area where the use of genetic testing has increased rapidly is in the area of hereditary cancer, particularly in relation to hereditary breast/ovarian and hereditary bowel cancer syndromes. Genetic screening may also be of help in determining the chance of developing renal tumors in these disorders. Molecular diagnostic laboratories have developed numerous methods to scan DNA and/or RNA for mutations in specific disease genes or, in certain disorders such as cystic fibrosis, to screen for specific known mutations that cause disease in a high percentage of affected individuals. The current mainstay for molecular diagnosis involves sequence-based protocols that examine the exons and adjacent intronic regions of specific genes.

Item does not contain fulltext Familial adenomatous polyposis (FAP) is an autosomal dominant form of intestinal polyposis and colorectal cancer caused by germ-line mutations in the adenomatous polyposis coli (APC) gene. The term Gardner's syndrome is used to describe extracolonic manifestations, such as osteomas, skin cysts, congenital hypertrophy of the retinal pigmented epithelium (CHRPE), and desmoid tumours (aggressive fibromatosis), that are especially prominent in families with FAP. We postulate that a ciliary dysfunction is the underlying pathogenetic mechanism of extraintestinal manifestations in patients with FAP. This postulation is based on the presence of common clinical manifestations (ie, cysts, retinal abnormalities, and fibrosis) in Gardner's syndrome and cilia-related disorders. Additionally, both APC and the cilia have degradation of beta-catenin as the common downstream target in the Wnt-signalling pathway. Mutations in APC causing Gardner's syndrome are clustered in a region encoding a series of amino-acid repeats responsible for the binding to beta-catenin. Proofs of principle that beta-catenin could be the key mediator of the ciliary disorder also rely in the findings that overexpression of beta-catenin induces polycystic kidney disease, and CHRPE phenotypes in animal models. Other candidates for the common link between Gardner's syndrome and cilia-related disorders are the APC-binding proteins: end-binding protein 1 (EB1) and kinesin-family-member 3a (KIF3a), both of which are ciliary proteins involved in intraflagellar transport. Finally, pathogenetic similarities between some ciliopathies and extraintestinal tumours in FAP suggest a cilia defect. Understanding extracolonic manifestations in the context of FAP as a ciliary disorder might add new therapeutic options for patients with Gardner's syndrome.

Contains fulltext : 80101.pdf (Publisher’s version ) (Closed access) Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocation of aquaporin-2 to the apical membrane. Moreover, in contrast to plasma membrane V2R, degradation of intracellular V2R mutants is not increased by their activation. Our data reveal that G protein-coupled receptors (GPCRs) normally active at the plasma membrane can be activated intracellularly and that intracellular activation does not induce their degradation; the data also indicate that nonpeptide agonists constitute highly promising therapeutics for diseases caused by misfolded GPCRs in general, and NDI in particular.

Contains fulltext : 80004.pdf (Publisher’s version ) (Closed access) AIM: Due to the occasional association pathological fractures and osteoporosis we evaluated four patients with cutis laxa syndrome for skeletal anomalies. PATIENT/METHODS: We prospectively evaluated four patients, a male and a female child and a brother-sister sib pair, with dysmorphic features, growth delay, joint anomalies, psychomotor retardation and congenital cutis laxa. The clinical features and the family history were suggestive for autosomal recessive cutis laxa syndrome type II, partially overlapping with geroderma osteodysplastica. Skeletal survey, sequential bone density measurements, endocrine and metabolic investigations were performed including N- and O-linked glycosylation analysis. ATP6V0A2 and FBLN5 mutations were ruled out in all patients. RESULTS: All children were diagnosed with significantly decreased bone density, especially in the lumbar spine, including spontaneous vertebral and rib fractures in three children. Following 24 months of bisphosphonate treatment a total restitution of bone density was observed in three cases and no relapse was detected in the 2-year follow-up period. A spontaneous improvement was found in one female during puberty. CONCLUSION: Bone disease might occur early in the course in autosomal recessive cutis laxa syndrome. We report on a significant clinical improvement and stabilization in our patients following bisphosphonate therapy. We suggest early, systemic evaluation and follow up of bone density in all children presenting with inherited cutis laxa.

Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent. ispartof: Orphanet journal of rare diseases vol:3 issue:1 ispartof: location:England status: published

Wolf-Hirschhorn syndrome is characterized by severe growth and mental retardation, microcephaly, seizures and 'Greek helmet' facies, caused by partial deletion of the short arm of chromosome 4. Growth charts are given from 0-4 years of age, based on the study of 101 individuals. Use of these specific growth charts is recommended, because standard growth charts are inapplicable for patients with WHS. ispartof: European Journal of Pediatrics vol:167 issue:7 pages:807-810 ispartof: location:Germany status: published

Contains fulltext : 70163.pdf (Publisher’s version ) (Closed access) A homozygous mutation of the CNTNAP2 gene has been associated with a syndrome of focal epilepsy, mental retardation, language regression and other neuropsychiatric problems in children of the Old Order Amish community. Here we report genomic rearrangements resulting in haploinsufficiency of the CNTNAP2 gene in association with epilepsy and schizophrenia. Genomic deletions of varying sizes affecting the CNTNAP2 gene were identified in three non-related Caucasian patients. In contrast, we did not observe any dosage variation for this gene in 512 healthy controls. Moreover, this genomic region has not been identified as showing large-scale copy number variation. Our data thus confirm an association of CNTNAP2 to epilepsy outside the Old Order Amish population and suggest that dosage alteration of this gene may lead to a complex phenotype of schizophrenia, epilepsy and cognitive impairment.

Roepman, Ronald/0000-0002-5178-8163; van Beersum, Sylvia E.C./0000-0002-4552-2908; Coene, Karlien/0000-0001-9873-1458; Dibooglu, Sel/0000-0002-3865-5868; Moens, Cecilia/0000-0002-1099-0728; Davis, Erica/0000-0002-2412-8397; Otto, Edgar/0000-0002-2387-9973; Katsanis, Nicholas/0000-0002-2480-0171 WOS: 000261006900002 PubMed: 18950740 Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD) are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function Mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GSTpulldown experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for Studying extragenic modifiers in JSRD and other ciliopathies. US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K23NS45832]; NCRRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [5KI.2RR025015]; University of Washington Center on Human Development and DisabilityUniversity of Washington [P30HD02274]; Howard Hughes Medical InstituteHoward Hughes Medical Institute; March of Dimes EndowmentMarch of Dimes; Dutch Kidney Foundation [C04.2112]; EVIGENORETEuropean Union (EU) [LSHG-CT-2005 512036]; Netherlands Organisation for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [Vidi-91786396]; [K24HD46712]; [P30ES07033]; [021.001.014] We thank all the participating families with Joubert syndrome and M. Landsverk, R. Howard, J. Adkins, and members of the Moens laboratory for expert technical assistance and helpful discussions. This work was supported by the US National Institutes of Health (grants K23NS45832 to M.A.P, K24HD46712 to I.A.G., NCRR 5KI.2RR025015 to D.D., and P30ES07033 to F.M.F.), the University of Washington Center on Human Development and Disability (P30HD02274 to D.D., M.A.P, and I.A.G.), Howard Hughes Medical Institute (to C.B.M.), the University of Washington Center on Ecogenetics and Environmental Health and the March of Dimes Endowment for Healthier Babies at Children's Hospital in Seattle (to D.D., M.A.P., and I.A.G.), as well as grants from the Dutch Kidney Foundation (C04.2112 to N.V.A.M.K. and R.R.), EVIGENORET (LSHG-CT-2005 512036 to R.R.), and the Netherlands Organisation for Scientific Research (NWO Vidi-91786396 to R.R. and NWO Toptalent-021.001.014 to K.L.M.C.).