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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.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.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.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.

Microdeletions of Xp22.3 are associated with contiguous gene syndromes, the extent and nature of which depend on the genes encompassed by the deletion. Common symptoms include ichthyosis, mental retardation and hypogonadism. We report on a boy with short stature, ichthyosis, severe mental retardation, cortical heterotopias and Dandy-Walker malformation. The latter two abnormalities have so far not been reported in terminal Xp deletions. MLPA showed deletion of SHOX and subsequent analysis using FISH and SNP-arrays revealed that the patient had an 8.41 Mb distal deletion of chromosome region Xp22.31 --> Xpter. This interval contains several genes whose deletion can partly explain our patient's phenotype. His cortical heterotopias and DWM suggest that a gene involved in brain development may be in the deleted interval, but we found no immediately obvious candidates. Interestingly, further analysis of the family revealed that the patient had inherited his deletion from his mother, who has a mos 46,X,del(X)(p22)/45,X/46, XX karyotype.

Two children with a partial monosomy 6q are reported: a girl with an interstitial deletion [46, XX, del(6)(q16.2q23.1)], and a boy with a terminal deletion [46, XY, del(6)(q25.1)]. Both children presented with developmental delay, facial dysmorphism and a cardiac defect. The patients have been studied using G banding and cosmid probes specific for the long arm of chromosome 6. Clinical data are compared with patients reported in the literature.

Fluorescent in situ hybridization with probes specific for a chromosomal subregion and chromosome-specific libraries (chromosome painting) are important new methods for assessing chromosome rearrangements. In this paper we present four patients with additional chromosomal material on chromosome 8p who have been studied using G-banding techniques, chromosome painting and FISH with cosmid probes specific for the region 8p23.1-->8pter. In all cases we found a partial inversion duplication of 8p along with a deletion of the region 8p23.1-->8pter.

We report one patient with a de novo inversion duplication 18 (pter-->cen) and two cases of direct tandem duplication 18 (pter-->cen), one due to maternal inheritance and the other arising as mosaicism of unknown origin. The duplications are demonstrated by high resolution banding. They were verified by in situ hybridization with a paint specific for chromosome 18 and with DNA probe LI.84 specific for the centromere region of chromosome 18. FISH with the genomic DNA probe pHRR68 specific for 18p11.32 revealed a subtle deletion concomitantly involved in the case of inversion duplication 18p. The patients exhibit slight developmental delay/moderate mental retardation and only a few dysmorphic features. The literature on trisomy 18p is reviewed and the present cases are compared to it.

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.

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.

Institute for Growth and Development, University of Maastricht, The NetherlandsWe report on monozygotic (MZ) twins with adenovomos46,XX,der(15)t(11;15)(p12;p11.2)/46,XXkaryotypevaryingindifferenttissues.The clinical presentation and findings at thecytogenetic level are described. One of theinfants had definite minor anomalies atbirth, also found in other cases of trisomy of11p resembling the Beckwith–Wiedemannsyndrome. Theoretical backgrounds regard-ing the string of events leading to thecytogenetic findings in these twins andthe various factors that might have con-tributed to the dissimilarities in phenotypebetween these twins are discussed.

We report on a newborn boy with a congenital heart defect, severe pre- and postnatal growth retardation, feeding problems, facial anomalies and unilateral hydronephrosis. Cytogenetic analysis showed extra chromosomal material on the short arm of one chromosome 15 that at first sight could be mistaken for a chromosomal variant and could not be identified with conventional banding techniques. Chromosome analysis of the parents showed that both had a normal karyotype. Microdissection of five copies of the aberrant chromosome 15, amplification of the dissected chromosomal material by DOP-PCR and subsequent reverse painting was performed and disclosed that the patient had a de novo 46,XY,der(15)(6pter6p22.1::15p1215qter) karyotype with a “pure” trisomy of chromosome region 6p22.16pter. The associated phenotypic anomalies are compared with other reported cases with a distal duplication of chromosome 6p. © Wiley-Liss. Inc.

We report on a 2-year-old boy presenting with growth and psychomotor retardation and facial anomalies, including a flat face with prominent forehead, a flat nasal bridge and flat occiput, unusually long curved eyelashes, and a thin upper lip with down-turned corners of the mouth. Analysis of GTG-banded chromosomes demonstrated that the patient had extra chromosomal material in the long arm of one chromosome 5. This chromosome aberration was characterized further using microdissection and FISH with band-specific probes and a de novo direct duplication (5)(q31.3q33.3) was shown to be present. We have compared this case with others known to be partially trisomic for chromosome 5q reported in the literature. © 2001 Wiley-Liss. Inc.

Chromosome analysis was performed in a 34-year-old man who was phenotypically normal except for oligoasthenozoospermia. In this patient, analysis of GTG-banded chromosomes showed in one chromosome 8 additional chromosomal material of unknown origin. To characterize the aberrant chromosome more precisely, a paint specific for chromosome region 8pter-->8p23.1 was generated by microdissection and degenerated oligonucleotide primed-polymerase chain reaction (DOP-PCR) and used as fluorescence in situ hybridization (FISH) paint. After reverse painting, hybridization signals were only found on the short arm of the two chromosomes 8, with an enlarged signal on the derivative chromosome 8. The duplication was characterized further with band-specific FISH probes. We concluded that (part of) chromosome region 8p23.1-->p23.3 was duplicated. Chromosome analysis of the parents showed that the dup(8) was of maternal origin and that the fertile brother of the index patient also was a carrier of the chromosome aberration. There was no history of miscarriages. We suggest that duplication of region 8p23.1-->p23.3 can be regarded as euchromatic variant or duplication with no phenotypic effect.

In a 6-year-old girl referred because of mild motor delay and hyperextensible joints, chromosome analysis disclosed a derivative chromosome consisting of end-to-end fusion of chromosomes 2 and 14. Two cell lines existed in which this telomere association was present, one with a 45,XX,tas(2;14)(q37;p11) karyotype and one with a 45,XX,tas(2;14) (q37;q32) karyotype. The cell line with the telomeric fusion of 2q and 14p was present in 90% of the cells; a telomeric fusion of 2q and 14q was seen in the remaining 10% of the cells. In both association complexes, only the centromere of chromosome 14 was active. Fluorescence in situ hybridization with telomere and subtelomere probes disclosed no deletion of chromosomal material. Microsatellite analysis showed that the patient had a normal biparental contribution of chromosomes 14.

We report on two mentally retarded adults with an unbalanced karyotype resulting from a familial balanced translocation between chromosomes 8 and 21, t(8;21)(p21.1;q22.3). This translocation has not been reported before. Both patients had partial trisomy 8p and partial monosomy 21q. Fluorescence in situ hybridisation (FISH) was used to determine the chromosomal breakpoints more precisely. The first patient showed mild mental retardation and facial dysmorphism, slightly resembling the earlier described trisomy 8p phenotype. He did not resemble his affected niece, who was more severely retarded, had serious epilepsy, but lacked the facial dysmorphism. Comparing the data of both patients with published reports of trisomy 8p, marked differences were found between patients with an inversion duplication (inv dup) 8p, patients with partial trisomy 8p caused by an unbalanced translocation, and our patients. Inv dup(8p) causes a recognisable phenotype, whereas the phenotype of trisomy 8p resulting from a translocation is much more variable, probably because of the accompanying monosomies. However, even the same abnormal karyotype can cause different phenotypes, as our patients show. Counselling carriers of the balanced translocation in this family, a 20-25% recurrence risk for unbalanced offspring and a 25% risk for miscarriages seem appropriate.

A simple and efficient method for the dissection of (marker) chromosomes, (micro)nuclei, and chromosome regions is presented. Before microdissection, metaphases are overlaid with milli-Q water to rehydrate the chromosomes, which makes them soft and sticky. The dissected chromosome fragments are dissolved without proteinase-K or topoisomerase treatment and directly amplified using a degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR). The advantages of this microFISH method over previously reported methods are: (1) microdissection in this way is very fast; (2) a chromosome, marker, (micro)nucleus, or chromosome region is collected as a whole using only one microneedle; (3) the dissected material sticks tightly to the needle without the risk of getting lost; (4) no Sequenase is used in the DOP-PCR reaction which reduces the risk of contamination.

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.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).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.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.

Microdissection and fluorescence in situ hybridisation (FISH) were used to elucidate the nature of a complex chromosome translocation, after GTG banding failed in the complete characterisation of the structural rearrangement between chromosomes 6 and 12. These chromosomes were painted with chromosome specific paints and one of the chromosome regions involved in the translocation was isolated by microdissection. Ten copies of the microdissected region were collected with microneedles from GTG banded metaphases, transferred to a collecting drop, and amplified by means of DOP-PCR. The PCR product was labelled with biotin-14-dATP and used as a FISH probe for hybridisation to normal metaphase chromosomes and metaphase chromosomes of the patients (microFISH). FISH with this chromosome region specific painting probe and with chromosome band specific probes enabled the characterisation of a complex chromosome rearrangement with five breakpoints in two chromosomes. This resulted in the following karyotype: 46,XY,t(6;12)(6pter--> 6q12::12q24.1-->12qter;12qter-->12q13.3:: 6q16.2-->6q26::12q13.3-->12q24.1::6q12--> 6q16.2::6q26-->6qter).

We report on clinical and cytogenetic data on 5 children and 2 adults with a de novo inverted duplication of the short arm of chromosome 8, and we give a review of 26 patients from the literature. The clinical picture in young children is characterized by minor facial anomalies, hypotonia, and severe developmental delay. In older patients the facial traits are less characteristic, spastic paraplegia develops, and severe orthopedic problems are frequent. Psychomotor retardation is always severe-to-profound. Duplication of 8p21-p22 results in a clinically recognizable multiple congenital anomalies/mental retardation (MCA/MR) syndrome. It is shown that in all patients examined, the duplication was accompanied by a deletion of the most terminal part of 8p.

We report on 2 girls with mosaic tetrasomy 8p. Patient 1 showed the extra iso 8p chromosome in 20% of cultured lymphocytes and 18% of cultured fibroblasts [46,XX/47,XX, + i(8p)]. She presented with growth retardation, mild facial alterations, and motor developmental delay. Patient 2 presented with developmental delay, hypotonia, and slight facial alterations; she had the extra iso 8p chromosome in 94% of cultured peripheral lymphocytes. The patients are compared to the 6 previously reported cases. In our experience, the presently reported patients clinically resemble children with inv dup(8)(p21-p22) and patients with mosaic trisomy 8. © 1994 Wiley-Liss, Inc.

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.

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.

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.

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.

We report on a patient with a de novo 15q24q26.1 interstitial deletion. She presented with developmental delay, behavioral characteristics, and mild dysmorphism with very blue irises. We review the limited literature of interstitial 15q deletions. There was no distinct phenotypic overlap between these two cases in literature and the present patient. Additional reports are necessary in order to establish a possible recognizable deletion 15q24q26.1 phenotype.

Item does not contain fulltext We report on the clinical and cytogenetic data of a large family with an unbalanced insertion translocation (3;5)(q25.3;q22.1q31.3). Analysis of GTG-banded chromosomes demonstrated that unbalanced inheritance of a parental insertion translocation caused either a partial deletion or duplication 5q in this family. The derivative chromosomes were characterized further using microdissection and FISH with band-specific probes. The clinical picture of the proband with a partial deletion of chromosome 5 was characterized by moderate psychomotor retardation, mild facial dysmorphism, cleft palate, and single transverse crease. The family members with a partial duplication of chromosome 5 were borderline intelligent, had mild facial dysmorphism, a cardiac anomaly, and a high-pitched voice. The unbalanced carriers were compared with patients reported in the literature with a duplication or deletion of chromosome region 5q22.1 --> 5q31.3.

Objective This study aimed to identify a marker chromosome and characterize the short arm of a derivative chromosome 5 in a foetus with the following karyotype: mos 47,XX,del(5)(p?),+i(5)(p10)[50]/48,XX,del(5)(p?),+i(5)(p10),+mar[25]. Method Amniocentesis was performed in the 26th week of pregnancy because of ultrasound abnormalities (polyhydramnion and decreased amount of gastric filling). All classic banding techniques were performed. FISH and microdissection combined with reverse painting were used to reveal the exact origin of the marker and any extra material on the deleted chromosome 5p. The parents decided to continue the pregnancy and we compared the clinical features of the child born in week 34 with data from the literature on trisomy 5p. The possible contribution of trisomy of the centromeric region of chromosome 8 and trisomy 8p23.38pter to this clinical picture was evaluated. Results GTG banding showed one normal and two aberrant chromosomes 5 [del(5)(p?) and i(5)(p10)] in all the cells examined. Furthermore, a supernumerary marker chromosome was present in approximately 30% of the cells. The marker was CBG positive and positive with the pancentromere probe, but dystamicinA/DAPI negative. It did not contain NOR-positive satellites. FISH proved this marker to be derived from the centromeric region of chromosome 8. MicroFISH disclosed the aberrant chromosome 5 as der(5)t(5;8)(p10;p23.3). The parent's karyotypes were normal. The baby showed the characteristic features of trisomy 5p syndrome. She died at the age of 15 days after cardiorespiratory arrest. Conclusion The karyotype was interpreted as mos 47,XX,add(5)(p10).rev ish der(5)t(5;8)(p10;p23.3),+i(5)(p10) (WCP5+,D5S23+)[50]/48,XX,add(5)(p10).rev ish der(5)t(5;8)(p10;p23.3),+i(5)(p10)(WCP5+,D5S23+),+mar.ish 8(p10q10)(D8Z2+,WCP8-)[25]. Therefore, the baby had complete trisomy 5p, with trisomy of the distal part of 8p and of the centromeric region of chromosome 8. The clinical significance of de novo marker chromosomes is a major problem in prenatal counselling. Molecular cytogenetic tools such as FISH and microFISH are indispensable for characterizing markers and determining the breakpoints more precisely in deleted chromosomes. Copyright © 2003 John Wiley & Sons, Ltd.

Chromosome analysis in a couple referred because of two spontaneous abortions showed a normal 46,XX karyotype in the 28-year-old female and an aberrant Y chromosome with an enlarged short arm in the 30-year-old male. Subsequent chromosome analysis showed that his 33-year-old brother was carrier of the same Y chromosome aberration. Further characterization of the aberrant Y chromosome with FISH using probes specific for chromosome bands Yp11.32, Yq11.2, the centromere and the subtelomeric region of the p-arm of the Y chromosome showed that chromosome band Yq11.2 was duplicated and inserted in the p-arm of the Y chromosome. Combining the results of the analysis of GTG-banded chromosomes and of the FISH analysis we conclude that both patients have a 46,X,ins dup(Y)(pter --> p11.23::q12 --> q11.1::p11.23 -->) karyotype. The clinical and cytogenetical findings are reported and discussed.

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.

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.

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.

Common clinical features of patients with 3q23 deletion include the phenotype of BPES (blepharophimosis, ptosis, epicanthus inversus and telecanthus syndrome), growth and mental retardation, microcephaly, ear and nose dysmorphism and joint and digit abnormalities. We report on a 3-year-old girl with the phenotype of BPES, mental retardation, facial dysmorphism and camptodactyly. In addition, she had a congenitally small larynx and severe, chronic feeding difficulties. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q23-q25) Conclusion Congenital laryngostenosis and severe feeding problems may be part of the clinical syndrome caused by chromosome 3q23 deletion.

Microdissection combined with fluorescence in situ hybridization (micro-FISH) was used to visualize deletions in rearranged human chromosomes and in a de novo translocation. In each experiment five copies of a structurally aberrant chromosome or of the two chromosomes involved in the de novo translocation were isolated by microdissection and amplified using DOP-PCR. The PCR products were then used as probes for FISH to metaphase chromosomes of three patients. After reverse chromosome painting, the structurally aberrant chromosomes were completely painted, and the region deleted in the aberrant chromosomes was visible in the normal chromosomes. The smallest deletion that could be demonstrated this way was a microdeletion of ∼6 × 106 bp, which is frequently reported in Angelman and Prader-Willi syndromes.

We report on a mother and her two sons who had a direct duplication of chromosome region 8p22-8p23.1 without dysmorphic features and only mild mental retardation. The patients have been studied using G banding, chromosome painting, and FISH using cosmid probes specific for the region 8p23.1-8pter. Comparison of the phenotypes of our patients and of published patients with an inversion duplication of the short arm of chromosome 8 indicates that trisomy for chromosome band 8p21 causes the more severe clinical picture in the latter.

The vast majority of individuals with the fragile X syndrome show expanded stretches of CGG repeats in the 5' non-coding region of FMR1. This expansion coincides with abnormal methylation patterns in that area resulting in the silencing of the FMR1 gene. Evidence is accumulating that this directly causes the fragile X phenotype. Very few other mutations in FMR1, causing the fragile X phenotype have been reported thus far and all concerned isolated cases. We, however, report a family, in which 11 individuals have a deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene. Although fragile X chromosomes were not detected, all 4 affected males and 2 of the carrier females show characteristics of the fragile X phenotype. Using RT-PCR we could demonstrate that FMR1 is not expressed in the affected males, strongly suggesting that the FMR1 promoter sequences 5' to the CGG repeat are missing. The deletion patients have approximately 45 CGG repeats in their FMR1 gene, though not interspersed by AGG triplets that are usually present in both normal and expanded repeats. It is hypothesized that prior to the occurrence of the deletion, an expansion of the repeat occurred, and that the deletion removed the 5' part of the CGG repeat containing the AGG triplets. Transmission of the deletion through the family could be traced back to the deceased grandfather of the affected males, which supports the hypothesis that the FMR1 gene product is not required for spermatogenesis. Finally, the data provide additional evidence that the fragile X syndrome is a single gene disorder.

Partial trisomy 16p is a rare chromosomal anomaly in newborns: of the fewer than 30 carrier patients so far reported, most were born to parents with a balanced translocation involving the p arm of chromosome 16.1 Pure partial trisomy 16p has been reported in seven patients,2–6 three of whom (all showing behavioural problems with autistic traits) carried a tandem duplication of the (16)(p11.2–p12) region4,6; minor dysmorphisms were reported in only one patient.4 Linkage studies indicated chromosome 16p as a major location for autism susceptibility genes,7 while association was reported between autistic traits and attention deficit or hyperactivity disorders mapping to the 16p13 band.8 In addition TSC2, one of the genes responsible for tuberous sclerosis, a syndrome often associated with autistic traits, maps to the same cytogenetic band.9 We report the clinical phenotype and refined molecular cytogenetic characterisation of a patient carrying a (16)(p11.2p12.2) duplication. By extending the FISH analysis to a previously described patient with an apparently similar chromosomal rearrangement,6 we found that low copy repeats map to the 16p11.2 and 16p12.2 duplication endpoints, suggesting non-allelic homologous recombination as the pathogenetic mechanism. This finding is consistent with the non-random occurrence of the observed chromosomal rearrangement and the high frequency of segmental duplications identified throughout chromosome 16.10–12 We also inferred from genotype-phenotype correlation studies that genes involved in autism susceptibility are located within the duplicated region. Patient 1 is a 25 year old man, the first son of unrelated parents. At the time of his birth, his mother was aged 30 and his father 29 years. He was born at term with a weight of 2.550 kg (3rd centile). The father suffered from alcohol misuse and left the family when the patient was 12 years old. Because of …