Estimates of live birth prevalence of children with Down syndrome in the period 1991-2015 in the Netherlands.

BACKGROUND: In Western countries, increasing maternal age has led to more pregnancies with a child with Down syndrome (DS). However, prenatal screening programs, diagnostic testing and termination of pregnancy influence the actual DS live birth (LB) prevalence as well. The aim of this study is to examine these factors in the Netherlands for the period 1991-2015. In our study, we establish a baseline for DS LB prevalence before non-invasive prenatal testing will be made available to all pregnant women in the Netherlands in 2017. METHODS: Full nationwide data from the Dutch cytogenetic laboratories were used to evaluate the actual DS LB prevalence. In addition, nonselective DS prevalence, which is the DS LB prevalence that would be expected in absence of termination of pregnancies, was estimated on the basis of maternal age distribution in the general population. RESULTS: Because of an increase in maternal age, nonselective DS prevalence increased from around 15.6 [95% confidence interval (CI) 13.9-17.4] per 10 000 LBs in 1991 (311 children in total) to around 22.6 (95% CI 20.3-24.9) per 10 000 in 2015 (385), the increase levelling off in recent years. Actual LB prevalence rose from around 11.6 (95% CI 10.9-12.2) per 10 000 in 1991 (230 children) to an estimated peak of 15.9 (95% CI 15.6-16.2) per 10 000 in 2002 (322), gradually decreasing since to 11.1 (95% CI 10.8-11.5) per 10 000 in 2015 (190). Reduction of DS LBs resulting from elective terminations had been fairly constant between 1995 and 2002 at around 28% and rose afterwards from 35% in 2003 to around 50% in 2015. CONCLUSIONS: In spite of expansion of antenatal screening in the Netherlands in the 1990s and early 2000s, actual DS LB prevalence increased during this period. However, after 2002, this trend reversed, probably because of informing all pregnant women about prenatal testing since 2004 and the implementation of a national screening program in 2007.

Psychopathology in adults with 22q11 deletion syndrome and moderate and severe intellectual disability.

BACKGROUND: 22q11 deletion syndrome (22q11DS) is associated with mild or borderline intellectual disability (ID). There are hardly any reports on subjects with 22q11DS with moderate or severe ID, and therefore its behavioural and psychiatric characteristics are unknown. METHOD: We describe behavioural and psychiatric characteristics of 33 adults with 22q11DS and a Full-Scale IQ (FSIQ) below 55. Participants were divided into two groups: one group having a FSIQ ≤ 55 caused by intellectual decline (n = 21) and one group with a FSIQ ≤ 55 who had always functioned at this level (n = 12). RESULTS: High scores on psychopathology sub-scales were found for both subgroups. 22q11DS patients with intellectual decline showed higher rates of co-morbid psychopathology, particularly psychosis. Furthermore, psychosis and intellectual decline were positive correlated. CONCLUSION: This is the first report addressing adult patients with 22q11DS and moderate to severe ID. Overall we found high levels of psychopathology with higher scores of psychopathology in the intellectual decline group. Life time psychosis seems to be related to deterioration.

Fluorescence in situ hybridization and single nucleotide polymorphism of a new case with inv dup del(8p).

Fluorescence In Situ Hybridization and single nucleotide polymorphism of a new case with inv dup del(8p): Inverted duplication deletion of 8p [inv dup del(8p)] is a complex chromosome rearrangement leading among others to deletion of the chromosome region distal to the duplication in 8p. A new case with an inverted duplication deletion of 8p and the results of SNP-array analysis and fluorescence in situ hybridization (FISH) are reported here. Our results are in concordance with earlier reported inv dup del(8p) cases.

Identification of novel dyslexia candidate genes through the analysis of a chromosomal deletion.

Dyslexia is the most common childhood learning disorder and it is a significantly heritable trait. At least nine chromosomal loci have been linked to dyslexia, and additional susceptibility loci on other chromosomes have been suggested. Within two of these loci, DYX1C1 (15q21) and ROBO1 (3p12) have recently been proposed as dyslexia candidate genes through the molecular analysis of translocation breakpoints in dyslexic individuals carrying balanced chromosomal translocations. Moreover, genetic association studies have indicated a cluster of five dyslexia candidate genes in another linkage region on chromosome 6p22, although there is currently no consensus about which of these five genes contributes to the genetic susceptibility for dyslexia. In this article, we report the identification of four new dyslexia candidate genes (PCNT, DIP2A, S100B, and PRMT2) on chromosome region 21q22.3 by FISH and SNP microarray analyses of a very small deletion in this region, which cosegregates with dyslexia in a father and his three sons.

Prospective screening of patients with unexplained mental retardation using subtelomeric MLPA strongly increases the detection rate of cryptic unbalanced chromosomal rearrangements.

This study was designed to increase the diagnostic detection rate for subtelomeric unbalanced chromosomal rearrangements (UCRs) that are believed to cause 3-5% of all cases of mental retardation (MR), but often remain undetected by routine karyotyping because of limited resolution in light microscopy. Increased detection of such cryptic UCRs may be achieved by CGH- or SNP-array technology adapted for genome wide screening but these techniques are labor-intensive and expensive. We have implemented subtelomeric Multiplex Ligation-dependant Probe Amplification (MLPA), a relatively low cost and technically uncomplicated molecular approach, as a high throughput prospective screening tool for UCRs in MR patients. We prospectively studied a cohort of 466 MR patients and detected 53 aberrant MLPA signals. After exclusion of false-positives, potential familial polymorphisms and of non-cryptic UCRs also found in routine chromosome analysis, 18 cases or 3.9% of total could be confirmed as true cryptic subtelomeric UCRs. These were 6 terminal deletions, 8 unbalanced translocations, 3 Prader-Willi deletions and 1 subtelomeric interstitial deletion. This result increases our laboratory's detection rate in this patient cohort from 8.3% (without MLPA) to 12.2% (with MLPA), representing a 47% improvement. This study demonstrates that when applying MLPA in a routine cytogenetic diagnostic setting, a major increase of the diagnostic yield can be achieved.

Virilization of the external genitalia and severe mental retardation in a girl with an unbalanced translocation 1;18.

A female infant with dysmorphic facial features, psychomotor retardation, and clitoris hypertrophy is described. Molecular cytogenetic analyses revealed a de novo unbalanced translocation, causing partial monosomy 1p36 and partial trisomy 18q22. Monosomy 1p was confirmed by FISH, and trisomy of the distal part of chromosome 18q was demonstrated by microFISH. Gene copy number changes in these chromosomal regions were determined by array-CGH. The absence of a number of facial dysmorphic signs, and the presence of clitoris hypertrophy indicate that the combination of a del(1p36->pter) with a dup(18q22->qter) may lead to a unique phenotypic constellation. The findings at birth and at age 12 years in our patient are compared with genotype-phenotype correlations discussed in the literature.

The velocardiofacial syndrome in older age: dementia and autistic features.

Velocardiofacial syndrome (VCFS) is a syndrome with a known, but variable clinical and behavioural phenotype. Most reported cases are patients of a relatively young age. The development of the behavioural phenotype and psychopathology in older patients with VCFS is less known. We present a case of a 52 year old male patient with VCFS and a deletion in chromosome band 22q11.2. He presents with typical symptoms reported in the behavioural phenotype, autistic features and an overall deteriorating process, which fulfils the DSMIV criteria for dementia.

The use of two different MLPA kits in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is one of the most common recurrent copy-number variant disorder, caused by a microdeletion in chromosome band 22q11.2 and occurring with a population prevalence of 1 in 2000. Until today there has been no evidence that the size of the deletion has an influence on the clinical phenotype. Most studies report that 22q11DS is associated with mild or borderline intellectual disability. There are a limited number of reports on 22q11DS subjects with moderate or severe intellectual disability. In this study we describe 63 adult patients with 22q11DS, including 22q11DS patients functioning at a moderate to severe intellectual disabled level. Deletion size was established with an experimental Multiplex ligation-dependent probe amplification (MLPA) mixture (P324) in addition to the commonly used MLPA kit (P250). We compared deletion size with intellectual functioning and presence of psychotic symptoms during life. The use of the experimental MLPA kit gives extra information on deletion size, only when combined with the common MLPA kit. We were able to detect eleven atypical deletions and in two cases the deletion size was shorter than all other "typical ones". We conclude that the use of the experimental kit P324 gives extra information about the deletion size, but only when used together with the standard P250 kit. We did not found any relation of deletion size with intelligence or presence of psychosis.

Report of a patient with a trisomy of chromosome region 20q11.2-->20q12 and characterization with FISH.

We report on a 16-month-old boy presenting with psychomotor retardation, craniofacial anomalies and severe vision deficit. Analysis of GTG-banded chromosomes showed that the patient had extra chromosomal material in the long arm of one chromosome 20. This chromosome aberration was further characterized with FISH using a chromosome 20 specific paint and band-specific probes. A partial trisomy 20q was shown to be present, the karyotype being 46, XY, dup (20) (q11.2q12). The cytogenetic and clinical findings are compared with cases previously reported in the literature.

Velo-cardio-facial syndrome: clinical report of a 70-year-old woman.

A clinical report is presented of a 70-year-old female in whom, after more than 40 years residential psychiatric care, the diagnosis of velo-cardio-facial syndrome (VCFS) was ultimately established; the patient has a 46, XX.ish del (22)(q11.2q11.2)(D(22)S(75)-) karyotype. It is advocated that a rather specific psychopathological profile is present in patients with VCFS, for which the term psychopathological phenotype is introduced, that should include data from genetics, neuropathology, development, psychology, and psychiatry.

Duplication of chromosome region (16)(p11.2 --> p12.1) in a mother and daughter with mild mental retardation.

We report a 40-year-old female with mild mental retardation and behavior problems and her 6-year-old daughter. Chromosome analysis showed that both patients had a proximal duplication in the short arm of chromosome 16. The aberration was characterized further with band-specific probes, resulting in a 46,XX,dir dup(16)(pter --> p11.2::p12.1 --> qter) karyotype. The clinical and cytogenetical findings are compared to other patients with partial trisomy 16p reported in the literature.

Congenital hydrocephalus in clinical practice: a genetic diagnostic approach.

Congenital hydrocephalus is a common and often disabling disorder. The etiology is very heterogeneous. Little is known about the genetic causes of congenital hydrocephalus. A retrospective survey was performed including patients with primary congenital hydrocephalus referred to the Department of Clinical Genetics between 1985 and 2010 by perinatologists, (child) neurologists or pediatricians. Patients with hydrocephalus secondary to other pathology were excluded from this survey. We classified patients with primary congenital hydrocephalus into two main groups: non-syndromic hydrocephalus (NSH) and syndromic hydrocephalus (SH). Seventy-five individuals met the inclusion criteria, comprising 36% (27/75) NSH and 64% (48/75) SH. In 11% (8/75) hydrocephalus was familial. The cause of hydrocephalus was unknown in 81% (61/75), including all patients with NSH. The male-female ratio in this subgroup was 2.6:1, indicating an X-linked factor other than the L1CAM gene. In the group of SH patients, 29% (14/48) had a known cause of hydrocephalus including chromosomal abnormalities, L1 syndrome, Marden-Walker syndrome, Walker-Warburg syndrome and hemifacial microsomia. We performed this survey in order to evaluate current knowledge on the genetic etiology of primary congenital hydrocephalus and to identify new candidate genes or regulatory pathways for congenital hydrocephalus. Recommendations were made concerning the evaluation and genetic workup of patients with primary congenital hydrocephalus. We conclude that further molecular and functional analysis is needed to identify new genetic forms of congenital hydrocephalus.

Mosaic trisomy (8)(p22 --> pter) in a fetus caused by a supernumerary marker chromosome without alphoid sequences.

OBJECTIVE: Our objective was to characterise a marker chromosome in cultured amniocytes of a fetus with a mos 47,XX,+mar[3]/46,XX[14] karyotype. METHODS: The indication for prenatal cytogenetic analysis of cultured amniocytes was advanced maternal age. Classic banding techniques (GTG- and C-banding) were performed. Microdissection combined with reverse painting was used to disclose the exact origin of the marker; the result was confirmed by chromosome painting and FISH with band-specific probes. RESULTS: Analysis of GTG-banded chromosomes showed a small marker chromosome in 3 of the 17 colonies analysed. Subsequently, C-banding showed no alphoid sequences, suggesting the presence of a neocentromere. The parent's karyotypes were normal. After normal ultrasound findings, the parents decided to continue the pregnancy. Chromosome analysis in peripheral blood after birth demonstrated that the marker chromosome was present in 50% of the lymphocytes. Using microFISH, the marker was further characterised and appeared to be derived from chromosome region (8)(p22 --> pter). CONCLUSION: Accurate identification of the marker chromosome was very important for prenatal counselling. Combining the results of GTG- and C-banding analysis with the results of the (micro)FISH, we concluded that the patient's karyotype is: mos 47,XX,+mar.rev ish der(8)(p22 --> pter)[50]/46,XX[50].

Subtelomeric chromosome aberrations: still a lot to learn.

Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.

Striking facial dysmorphisms and restricted thymic development in a fetus with a 6-megabase deletion of chromosome 14q.

During routine ultrasound screening at 12 weeks 5 days of gestation, a nuchal translucency of 7 mm, an omphalocele, and fetal hydrops were found and prompted chorionic villus sampling at 13 weeks 2 days. Chromosome analysis showed an unbalanced karyotype with an abnormal chromosome 14. The mother was a carrier of a translocation karyotype 46,XX,t(13;14) (q34;q32.2). In the fetus this gave rise to a partial trisomy 13q and partial monosomy 14q (fetal karyotype: 46,XX,der[14]t[13;14][q34;q32.2]). By Array-CGH on DNA extracted from a postmortem skin culture, a duplication of approximately 1.7 Mbp of the distal part of chromosome 13q34 and a deletion of approximately 6.0 Mbp of the distal part of chromosome 14q32.2 was demonstrated. Postmortem findings after termination of pregnancy at 14 weeks 6 days included, among others, a severe hypoplasia of the median part of the maxilla, no recognizable nose, a broad median palatoschisis, nonlobulated lungs, a horseshoe kidney with multicystic dysplasia, and decreased development of cortical cellularity in the thymus. These clinical manifestations and autopsy findings of the fetus are compared with those of previously published cases and the possible involvement in this pathology of the YY1 and JAG2 transcription factors and the BCL11b and SIVA-1 regulators of thymic development is discussed.

Characterization of partial trisomy 9p due to insertional translocation by chromosomal (micro)FISH.

We describe a family with an insertion 12;9 translocation occurring in a balanced form in a mother and two sons, but in an unbalanced form in the proband, resulting in trisomy of chromosome region 9p22-->9p24. The proband manifests typical features of trisomy 9p; the clinical signs were mental and growth retardation, microcephaly, epicanthus, low-set ears, micrognathia, clinodactyly and hypoplastic phalanges of the fifth fingers, hypoplasia or absence of toenails, and extremely small genitals. The GTG-banded findings were confirmed using (micro)FISH. Intriguingly, the mother and the two carrier sons exhibited major learning difficulties that were not present in the non-carrier sister of the mother: this may be due to a gene disruption or induction of abnormal expression. Dysmorphic features were not present in the three carriers. We compare our clinical and cytogenetic findings with other cases of partial trisomy 9p reported in the literature.

Prenatal diagnosis of a karyotypically normal pregnancy in a mother with a supernumerary neocentric 13q21 -->13q22 chromosome and balancing reciprocal deletion.

An adult female patient with a history of miscarriages was found to be carrying a stable supernumerary chromosome. The patient also carried a reciprocal paracentric deletion in chromosome 13q21/22. Microdissection and reverse fluorescence in situ hybridization FISH revealed that this supernumerary chromosome was derived from region 13q21 --> 13q22. The presence of a neocentromere on this supernumerary chromosome was confirmed by the absence of detectable alpha satellite DNA using FISH and the presence of centromere proteins CENP-C and CENP-A using immunofluorescence. The absence of telomere sequences suggests that the marker is a ring chromosome (r(13)). FISH using ordered BACs from the chromosome region 13q21 --> 13q31 permitted the precise positioning of the r(13) chromosome and the corresponding deletion to chromosome bands 13q21.32 --> 13q22.2. BAC 280J7 from within the r(13) was used as a FISH probe for the prenatal analysis of amniocytes at 16 weeks of gestation, which revealed a normal karyotype for the fetus. This r(13) chromosome represents the first description of chromosome 13 of the rarer class of neocentric chromosomes that are derived from interstitial deletions. It represents the first example of prenatal diagnosis in a phenotypically normal female that was ascertained to carry a neocentric marker. The presence of such a neocentric marker/deletion karyotype in a parent presents unique possible karyotypic outcomes for conceptions and unusual challenges for genetic counseling.

A radiation hybrid map of the X-chromosome of the dog (Canis familiaris).

The dog serves as an animal model for several human diseases including X-chromosome diseases. Although the canine X-chromosome is one of the largest chromosomes in the dog, only a few markers have been mapped to it to date. Using a commercially available canine whole genome radiation hybrid (RH) panel we have localized 14 microsatellite markers, 18 genes and 13 STSs on the canine X-chromosome, extending the total number of mapped markers to 45 covering an estimated 830 cR. Out of these 45 markers, seven distinct groups of markers could be established with an average spacing of 18.8 cR(3000) and ten markers remained unlinked. Using FISH analysis, six markers could be mapped physically to the p- or q-arm of the X-chromosome. Combined with the FISH mapping, three RH groups could be assigned to the p-arm and two RH groups to the q-arm. Comparison with the human X-chromosome map revealed conserved synteny up to 234 cR (TIMP1-ALAS2-AR-IL2RG-XIST). We show here that the similarity of the canine and human X-chromosomes is the largest for any mammalian species beyond the primates.