[Show abstract][Hide abstract] ABSTRACT: Background:
The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome.
We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function.
We identified a single heterozygous missense variant, c.1337A>C (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome.
This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.
Preview · Article · Jan 2016 · Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to evaluate the etiology, the role of pubertal timing and most useful criteria for diagnostic workup in adolescents with growth failure.
Adolescents (n=182) aged 10.0–18.0 years underwent a standardized diagnostic protocol. Constitutional delay of growth and puberty (CDGP) was defined as late pubertal onset or a Tanner stage less than –2 SDS. Dutch and Finnish criteria for growth monitoring were retrospectively assessed.
In 13 children (7.1%) a specific diagnosis could be established. CDGP was diagnosed in 10% of patients aged ≥13 (girls) or ≥14 years (boys). Sensitivity to detect pathologic causes was 85% and 62% for, respectively Dutch and Finnish criteria for growth monitoring as used in younger children, but specificity was low (55%–59%).
In adolescents, pathological causes for growth failure and pubertal delay are common, and we recommend a combination of height SDS, distance to THSDS and growth deflection for deciding on further diagnostic testing.
No preview · Article · Jan 2016 · Journal of pediatric endocrinology & metabolism: JPEM
[Show abstract][Hide abstract] ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-asscoiated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905 + 1G > A) and the combined presence of three risk variants in DPYD (c.1905 + 1G > A, c.1129-5923C > G, c.2846 A > T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the novel p.G401R mutation is most likely minor. The clinical relevance of the p.D949V mutation was demonstrated in a cancer patient heterozygous for the c.2846 A > T mutation and a novel nonsense mutation c.1681C > T (p.R561X), experiencing severe grade IV toxicity. Our studies showed that the endogenous levels of uracil and the U/UH2 ratio are poor predictors of an impaired DPD activity. Loading studies with uracil to identify patients with a DPD deficiency warrants further investigation.
No preview · Article · Jan 2016 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
[Show abstract][Hide abstract] ABSTRACT: Aims:
To evaluate three guidelines for selecting short children for diagnostic workup in a general pediatric clinic.
All patients (n = 131) aged 3.00-9.99 years who were referred for growth failure to a general pediatric clinic were evaluated for their medical history and growth and examined. All of them underwent the same standardized diagnostic workup. Retrospectively, the criteria for the diagnostic workup from three guidelines (proposed in the Netherlands, Finland and the UK) were applied, and their sensitivity was assessed. A Dutch reference sample (n = 958) was used for calculating population specificity.
In 23 patients (17.6%), a pathological cause of their growth failure was found. The sensitivity of the original Dutch, Finnish and British guidelines was 73.9, 78.3 and 56.5% and their specificity 98.5, 83.7 and 95.8%, respectively. When adding recent growth deflection to the Dutch guideline, sensitivity increased to 87%, but specificity decreased markedly (to 87%).
The proposed cutoff values for height standard deviation score and distance to target height/mid-parental height, as used in the Netherlands and Finland, are effective for population growth monitoring, and superior to the monitoring algorithm in the UK. Growth deflection irrespective of height is an important sign of acquired growth disorders, but its specificity is too low for population screening.
Full-text · Article · Oct 2015 · Hormone Research in Paediatrics
[Show abstract][Hide abstract] ABSTRACT: Background:
Robin Sequence (RS) is usually defined as the combination of micrognathia, glossoptosis and upper airway obstruction. No objective criteria to diagnose RS exist. To compare management strategy results, a single RS definition using objective criteria is needed. The most frequently used primary diagnostic tool for glossoptosis is awake Flexible Fiberoptic Laryngoscopy (aFFL).
To determine the reliability of the aFFL videos as an independent diagnostic tool itself, rather than on the complete evaluation of a patient.
Design, setting, participants:
All RS individuals from an existing cohort with an available aFFL video were included retrospectively. Thirty age-matched patients without pathologic findings on aFFL were used as controls. aFFL videos were scored by six otolaryngologists as: a. Marked glossoptosis, b. Mild glossoptosis, c. Severity unknown, d. No glossoptosis, e. Insufficient video quality. Videos were anonymized and rated twice, in altered sequences, after a washout period of minimally 2 weeks.
Main outcome measures:
Inter-rater and intra-rater agreement.
26 videos of 16 RS patients and 30 videos of controls were included. Inter-rater agreement was fair in the whole group (κ: 0.320) and RS group (κ: 0.226), and fair to moderate in determining presence of glossoptosis (total group κ: 0.430; RS κ: 0.302; controls κ: 0.212). The intra-rater agreement for presence of glossoptosis in RS was moderate (κ: 0.541).
aFFL offers fair to moderate inter-rater agreement, with moderate intra-rater agreement, in evaluating glossoptosis in RS. Using aFFL as the single tool in choosing management strategies in RS seems insufficient. There is need for a more reliable, patient friendly diagnostic tool or an internationally accepted aFFL scoring system, to diagnose glossoptosis in RS. This article is protected by copyright. All rights reserved.
No preview · Article · Oct 2015 · Clinical otolaryngology: official journal of ENT-UK; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery
[Show abstract][Hide abstract] ABSTRACT: Maternal Uniparental Disomy of chromosome 14 (matUPD(14)) resembles Prader-Willi syndrome. Since positive effects of growth hormone (GH) are observed in individuals with PWS, treatment with GH may be useful in individuals with matUPD(14) as well. The aim of this study was to investigate the effect of GH treatment on growth and body composition in children with matUPD(14).
Prospective observational study of GH treatment in two girls with matUPD(14) during 2 years, and spontaneous growth in another matUPD(14) girl of similar age.
Three girls (patient A, B and C, aged 8.9, 11.4 and 12.7 years respectively) with matUPD(14).
Patients A and B were treated with GH during two years. Patient C was not treated with GH, as she was diagnosed at an age at which she attained near-final height. Main outcome measures included height, weight, body proportions, IGF-1, bone age, DXA scan for body composition.
In both treated girls a considerable increase in height (from -2.3SD and -1.2SD to -1.2SD and -0.6SD, respectively) and IGF-1 levels (from +0.1SD and -1.4SD to +1.3SD and +0.9SD, respectively), and in patient A a decrease in weight (+1.2 SD to -0.7SD), and improved body composition (fat percentage from 51.5% to 45.4%). Both experienced improved muscle strength.
GH treatment in matUPD(14) cases can show beneficial effects on growth and body composition if started in time. Larger, international studies to determine detailed effectivity and side-effects are suggested. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Jun 2015 · Clinical Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Many current paediatric studies concern relationships between genes and environment and discuss aetiology, treatment and prevention of Mendelian and multifactorial diseases. Many of these studies depend on collection and long-term storage of data and biological material from affected children in biobanks. Stored material is a source of personal information of the donor and his family and could be used in an undesirable context, potentially leading to discrimination and interfering with a child's right to an open future. Here, we address the normative framework regarding biobanking with residual tissue of children, protecting the privacy interests of young biobank donors (0-12 years). We analyse relevant legal documents concerning storage and use of children's material for research purposes. We explore the views of 17 Dutch experts involved in paediatric biobank research and focus on informed consent for donation of leftover tissue as well as disclosure of individual research findings resulting from biobank research. The results of this analysis show that experts have no clear consensus about the appropriate rules for storage of and research with children's material in biobanks. Development of a framework that provides a fair balance between fundamental paediatric research and privacy protection is necessary.European Journal of Human Genetics advance online publication, 15 April 2015; doi:10.1038/ejhg.2015.59.
No preview · Article · Apr 2015 · European journal of human genetics: EJHG
[Show abstract][Hide abstract] ABSTRACT: Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of sixteen patients with CdLS-like features caused by mutations in SMC3. Modelling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared to typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼1-2% of CdLS-like phenotypes. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.
Full-text · Article · Jan 2015 · European Journal of HumanGenetics