De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield.

BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome.

BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.

Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis.

OBJECTIVE: Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances by aCGH compared to standard karyotyping and 22q11 microdeletion analysis by fluorescence in-situ hybridization (FISH), in the setting of prenatally-diagnosed cardiac malformations, has been reported in several studies. The objective of our study was to perform a systematic literature review and meta-analysis to document the additional diagnostic gain of using aCGH in cases of congenital heart disease (CHD) diagnosed by prenatal ultrasound examination, with the aim of assisting clinicians to determine whether aCGH analysis is warranted when an ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting. METHODS: Articles in PubMed, EMBASE and Web of Science databases from January 2007 to September 2014 describing CNVs in prenatal cases of CHD were included. Search terms were: 'array comparative genomic hybridization', 'copy number variants' and 'fetal congenital heart defects'. Articles regarding karyotyping or 22q11 deletion only were excluded. RESULTS: Thirteen publications (including 1131 cases of CHD) met the inclusion criteria for the analysis. Meta-analysis indicated an incremental yield of 7.0% (95% CI, 5.3-8.6%) for the detection of CNVs using aCGH, excluding aneuploidy and 22q11 microdeletion cases. Subgroup results showed a 3.4% (95% CI, 0.3-6.6%) incremental yield in isolated CHD cases, and 9.3% (95% CI, 6.6-12%) when extracardiac malformations were present. Overall, an incremental yield of 12% (95% CI, 7.6-16%) was found when 22q11 deletion cases were included. There was an additional yield of 3.4% (95% CI, 2.1-4.6%) for detecting variants of unknown significance (VOUS). CONCLUSIONS: In this review we provide an overview of published data and discuss the benefits and limitations of using aCGH. If karyotyping and 22q11 microdeletion analysis by FISH are normal, using aCGH has additional value, detecting pathogenic CNVs in 7.0% of prenatally diagnosed CHD, with a 3.4% additional yield of detecting VOUS.

A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion syndrome, is associated with syndromic intellectual disability.

We report a boy with severe syndromic intellectual disability who has a de novo mutation in the ZMYND11 gene. Arguments for pathogenicity of this mutation are found in cases from the literature, especially several with 10p15.3 deletions, harbouring ZMYND11. Additional reports of ZMYND11 mutations in cases with syndromic intellectual disability are needed before the ZMYND11 mutation identified in our case can be considered as definitely pathogenic.

A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient.

We report an Indonesian patient with bone fragility and congenital joint contractures. The initial diagnosis was Osteogenesis Imperfecta type III (OI type III) based on clinical and radiological findings. Because of (i) absence of COL1A1/2 mutations, (ii) a consanguineous pedigree with a similarly affected sibling and (iii) the existence of congenital joint contractures with absence of recessive variants in PLOD2, mutation analysis was performed of the FKBP10 gene, recently associated with Bruck syndrome and/or recessive OI. A novel homozygous deletion in FKBP10 was discovered. Our report of the first Indonesian patient with clinically Bruck syndrome, confirms the role of causative recessive FKBP10 mutations in this syndrome.

Osteogenesis Imperfecta: A Review with Clinical Examples.

Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures, with a severity ranging from subtle increase in fracture frequency to prenatal fractures. The first scientific description of OI dates from 1788. Since then, important milestones in OI research and treatment have, among others, been the classification of OI into 4 types (the 'Sillence classification'), the discovery of defects in collagen type I biosynthesis as a cause of most cases of OI and the use of bisphosphonate therapy. Furthermore, in the past 5 years, it has become clear that OI comprises a group of heterogeneous disorders, with an estimated 90% of cases due to a causative variant in the COL1A1 or COL1A2 genes and with the remaining 10% due to causative recessive variants in the 8 genes known so far, or in other currently unknown genes. This review aims to highlight the current knowledge around the history, epidemiology, pathogenesis, clinical/radiological features, management, and future prospects of OI. The text will be illustrated with clinical descriptions, including radiographs and, where possible, photographs of patients with OI.

Solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combined with asymmetric crying facies and postaxial lower limb reduction defects: a unique combination of features.

We report a boy with asymmetric crying facies and bilateral absence of the 5th ray of the feet. In addition, craniofacial computed tomography showed a solitary median maxillary central incisor in combination with a narrow apertura piriformis. To our knowledge this intriguing combination of congenital abnormalities has not been described before.

Epigenotype-phenotype correlations in Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. METHODS: A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. RESULTS AND CONCLUSIONS: The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

Classification of Osteogenesis Imperfecta revisited.

In 1979 Sillence proposed a classification of Osteogenesis Imperfecta (OI) in OI types I, II, III and IV. In 2004 and 2007 this classification was expanded with OI types V-VIII because of distinct clinical features and/or different causative gene mutations. We propose a revised classification of OI with exclusion of OI type VII and VIII since these types have been added because of genetic criteria (autosomal recessive inheritance) while the clinical and radiological features are indistinguishable from OI types II-IV. Instead, we propose continued use of the Sillence criteria I, II-A, II-B, II-C, III and IV for clinical and radiological classification of OI with additional mentioning of the causative mutated gene to this classification. OI type V and VI are still part of this revised classification, because of the distinguishing clinical/radiological and/or histological features observed in these types.

Down syndrome: a cardiovascular perspective.

This review focuses on the heart and vascular system in patients with Down syndrome. A clear knowledge on the wide spectrum of various abnormalities associated with this syndrome is essential for skillful management of cardiac problems in patients with Down syndrome. Epidemiology of congenital heart defects, cardiovascular aspects and thyroid-related cardiac impairment in patients with Down syndrome will be discussed.

Compound-heterozygous Marfan syndrome.

We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS). The proband of family 1 has the R2726W FBN1 mutation associated with isolated skeletal features on one allele and a pathogenic FBN1 mutation on the other allele. The phenotype of the compound-heterozygous probands appears to be more severe than that of their heterozygous family members which underlines the possibility that certain trans-located FBN1 mutations might act as modifiers of phenotype explaining some of the intrafamilial variability in Marfan syndrome.

Survival in SMA type I: a prospective analysis of 34 consecutive cases.

Thirty-four children with genetically proven SMA type I (age at onset <6 months, unable to sit during study period) were included in a 3-year prospective cohort study and neurologically followed-up until death or the end of the study. At the end of the study period 31/34 children had died. The median age at death was 176 days (95% Confidence Interval 150-214 days), the median survival from the time of diagnosis was 158 days (95% CI 137-232 days). The median survival after diagnosis did not differ significantly between children diagnosed at birth (median survival 137 days, 95% CI 111-232 days) and those diagnosed later (median survival 159 days, 95% CI 141-256), implying that SMA I cases with different ages of onset show the same progression rate of the disease. The number of SMN2 copies was not clearly correlated with survival duration, possibly because of lack of statistical power due to the small number of cases with 1 or 3 SMN2 copies. The three cases alive at the end of the study had either three or an unknown number of SMN2 copies, which is in agreement with previously described cases showing longer survival with increasing number of SMN2 copies. All deceased children died of respiratory insufficiency and/or an intercurrent lung infection, indicating that the susceptibility of the child with SMA type I to respiratory infections plays an important role in determining the survival.

Prenatal diagnosis of tetrasomy 9p in a 19-week-old fetus with Dandy-Walker malformation: a case report.

OBJECTIVE: The presentation of sonographic and perinatal findings of tetrasomy 9p. METHODS AND RESULTS: Chorionic villus sampling and amniocentesis were performed at 19 weeks of gestation because of the sonographic findings of Dandy-Walker malformation with bilateral ventriculomegaly. Cytogenetic analysis showed 47,XX,+i psu dic(9)(pter->q12::q12>-pter). The pregnancy was terminated at 20 weeks of gestation at the request of the parents. At post-mortem examination, the presumed hypoplasia of the vermis could not be confirmed for technical reasons. No other pathological findings were seen. CONCLUSION: From our experience and from the literature, we conclude that Dandy-Walker malformation is an important finding in tetrasomy 9p. Chromosomal studies should be carried out in fetuses with sonographically detected Dandy-Walker malformation, even in the absence of other abnormalities.

[Prenatal diagnosis for hereditary predisposition to mammary and ovarian carcinoma--defining a position]. / Prenatale diagnostiek naar de erfelijke aanleg voor mamma-/ovariumcarcinoom--een standpuntbepaling.

Prenatal testing for a BRCA mutation, the hereditary trait for mammary and ovarian carcinoma, with the intention of selective termination of pregnancy in case of a female carrier is a controversial ethical issue. Based on a review of the (limited) medical literature as well as of Dutch policy statements relating to this subject, the following conclusions and recommendations are proposed: (a) the decision to opt for prenatal BRCA testing and selective termination of pregnancy in case of a BRCA mutation in the foetus cannot immediately be judged unacceptable from an ethical point of view; (b) prenatal BRCA testing is morally defensible only in case of a female foetus and if the parents at least have the intention to terminate the pregnancy if the foetus is a carrier, although the final decision is in any case up to the parents only; (c) prental testing for a BRCA mutation should only be done after extensive counselling of the parents, during which not only the medical genetic aspects but also the ethical aspects of prenatal BRCA testing are discussed.

Fishing for a diagnosis.

A family with primary infertility and two members with mental retardation and subtle facial dysmorphism is described. In the two retarded persons chromosomal rearrangements (partial monosomy of chromosome 5 and partial trisomy of chromosome 7) were detected. One member of the family had died with major congenital malformations. Her fibroblasts had been stored and her chromosomes showed the inverse pattern (partial trisomy of chromosome 5 and partial monosomy of chromosome 7). It appeared that in familial mental retardation with or without congenital malformations FISH-techniques should be used to detect submicroscopic chromosomal aberrations, which are not detectable by routine chromosome studies.