Experts' opinions on the benefit of an incidental prenatal diagnosis of sex chromosomal aneuploidy: a qualitative interview survey.

OBJECTIVE: Incidental findings in prenatal diagnostic testing may or may not have clear prognostic significance for the phenotype. We studied experts' opinions of the benefit and disadvantage of an incidental prenatal diagnosis of a sex chromosomal aneuploidy (SCA). METHODS: We interviewed 16 experts in the field of counseling and treatment of people with SCA and asked 13 clinical geneticists and genetic associates about the clinical relevance of an incidental prenatal diagnosis of SCA. RESULTS: Most of the experts and clinical geneticists (87.5% and 76.9%, respectively) stated that an incidental prenatal diagnosis of SCA was a benefit for the child and the parents. They acknowledged the possibility of parental decisions to terminate pregnancy. Expert options in screening, training, and treatment of health, behavior, and fertility problems increase with an early diagnosis of SCA. CONCLUSION: Most experts favored an incidental prenatal diagnosis of SCA despite the complex counseling issues and their acknowledgment of possible parental decisions to terminate pregnancy. They believed the benefits greatly outweigh the disadvantages.

Intra-individual stability over time of standardized anti-Mullerian hormone in FMR1 premutation carriers.

BACKGROUND: Carriers of a premutation (CGG repeat length 55-200) in the fragile X mental retardation (FMR1) gene are at risk for primary ovarian insufficiency (FXPOI). The anti-Müllerian hormone (AMH) level acts as a useful marker of ovarian follicle reserve and, thus, may serve to predict when this ovarian reserve becomes too low to sustain ovarian function. We investigated the intra-individual variation of AMH levels over time for premutation carriers compared with non-carriers. METHODS: We determined AMH levels in blood samples from 240 women ascertained through fragile X families, of which 127 were premutation carriers and 113 were non-carriers. Linear mixed models were used to assess the effect of age and premutation status on AMH levels and to determine a modeled AMH value. The stability over time of the deviation of observed AMH levels from modeled levels, referred to as standardized AMH values, was assessed through correlation coefficients of 41 longitudinal samples. RESULTS: At all ages, premutation carriers exhibited lower AMH levels. For all women, AMH was found to decrease by 10% per year. The added effect of having a premutation decreased AMH levels by 54%. The deviation of an individual's AMH level from the modeled value showed a reasonable intra-individual correlation. The Pearson correlation coefficient of two samples taken at different ages was 0.36 (P = 0.05) for non-carriers and 0.69 (P = 0.01) for carriers. CONCLUSIONS: We developed a unique standardized AMH value, taking FMR1 premutation status and the subject's age into account, which appears to be stable over time and may serve as a predictor for FXPOI after further longitudinal assessment.

Parents' perspectives on the unforeseen finding of a fetal sex chromosomal aneuploidy.

OBJECTIVE: To investigate the parental perspectives of being confronted with an unforeseen fetal sex chromosomal aneuploidy (SCA), in light of the fact that this accidental finding is avoidable by rapid aneuploidy detection (RAD). METHODS: Exploratory qualitative interview study. We conducted 16 semi-structured interviews with parents who decided to continue pregnancy after the unforeseen finding of a fetal SCA. RESULTS: The communication of the unforeseen finding of SCA; the informed decision-making process concerning the pregnancy follow-up and the child and its future were the extracted themes. Parents were not prepared to accidental findings in routine prenatal diagnostics. All started an unguided search on the Internet. It is not at all clear whether parents have preference for an RAD test with X and Y probes Parents were satisfied with the post-test professional information they received to make an informed decision, whereas after birth questions still remained to be answered. CONCLUSION: Parents' perspectives may serve as major contributors to research on the question whether or not the X and Y probes should be standard included for purposes of RAD. The fact that RAD has the possibility to avoid accidental findings of SCAs, brings up the question whether any benefits outweigh the potential harms.

Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis.

BACKGROUND: The implementation of microarray analysis in prenatal diagnostics is a topic of discussion, as rare copy number variants with unknown/uncertain clinical consequences are likely to be found. The application of targeted microarrays limits such findings, but the potential disadvantage is that relevant, so far unknown, aberrations might be overlooked. Therefore, we explore the possibilities for the prenatal application of the genome-wide 250k single nucleotide polymorphism array platform. METHODS: Affymetrix 250k NspI single nucleotide polymorphism array analysis (Affymetrix, Inc., Santa Clara, California, USA) was performed on DNA from 38 prenatally karyotyped fetuses with ultrasound anomalies. Analyses were performed after termination of pregnancy, intrauterine fetal death or birth on DNA isolated from fetal or neonatal material. RESULTS: Aberrations were detected in 17 of 38 fetuses, 6 of whom with a previously identified chromosomal abnormality and 11 with previously normal or balanced karyotypes. Of the latter, the detected aberration occurred de novo and was considered of clinical relevance in five cases (16%), inherited from a healthy parent in four cases (12%), and de novo yet with unclear clinical relevance in two cases (6%). The clinically relevant abnormalities either were novel copy number variants (n=3) or concerned a uniparental disomy (n=2). CONCLUSION: In at least 16% of fetuses with ultrasound anomalies and a normal or balanced karyotype, causal (submicroscopic) aberrations were detected, illustrating the importance of the (careful) implementation of microarray analysis in prenatal diagnosis. The fact that the identified, clinically relevant, aberrations would have gone undetected with most targeted approaches underscores the added value of a genome-wide approach.

A small (sSMC) chromosome 22 due to a maternal translocation between chromosomes 8 and 22: a case report.

We report on a boy with partial trisomies for chromosomes 8 and 22 caused by the presence of a small supernumerary marker chromosome (sSMC), a der(22)t(8;22)(p22;q11.21), inherited from a t(8;22)(p22;q11.21) translocation carrier mother. He has mild mental retardation, unability to speak distinct words and several minor anomalies i.e. high forehead and hairline, telecanthus, upslanting palpebral fissures, depressed nasal bridge, nail hypoplasia, toe position anomaly and 5th finger clinodactyly. He has two maternal uncles and one maternal aunt with mental retardation. G-banding technique showed 47,XY,+mar whilst his mother's karyotype showed a balanced reciprocal translocation between the chromosomes 8 and 22. Fluorescence In Situ Hybridization (FISH) technique with probes for centromere 22 and 8pter were used to detect the origin of marker chromosome and confirmed the marker chromosome in the proband showing to be extra chromosomal material originated from chromosome 8 and 22. Additional genome wide microarray analysis, using the Affymetrix Nspl 250K SNP array platform was performed to further characterize the marker chromosome and resulted in a der(22)t(8;22)(p22;q11.21). Furthermore, cytogenetic analysis of three affected family members showed the same unbalanced translocation, due to 3:1 meiotic segregation. This indicated the viability of this unbalanced pattern and combined with the recurrent miscarriages by the proband's mother, the mechanism of transmitting extrachromosomal material is probably not a random process. Since, there is no similar translocation (8p;22q) reported and the chromosomal translocation largely exists of additional 8p22-8pter we compare the clinical outcomes with reported cases of 8p22-8pter triplication, although there is a part of genetic material derived from chromosome 22 present. This unique familial chromosome translocation case from Indonesia will give insight in the underlying mechanism of this recurrent chromosomal abnormality and clinical features of the patients will be compared to previously published cases.

[Alpha-foetoprotein assessment in amniotic fluid for the detection of neural tube defects: limited added value beyond week 20 ultrasound; retrospective study]. / Alfafoetoproteïnebepaling in vruchtwater voor de detectie van neuralebuisdefecten: beperkte meerwaarde boven de 20-wekenecho; retrospectiefonderzoek.

OBJECTIVE: To evaluate the diagnostic additional value of routine alpha-foetoprotein (AFP) assessment in amniotic fluid for the detection of neural tube defects (NTDs), compared with week 20 ultrasonographic examination. DESIGN: Retrospective. METHOD: We retrospectively determined AFP concentrations in amniotic fluid obtained from 7981 women who had undergone amniocentesis for karyotyping and AFP assessment. An AFP concentration greater than 2.5 times the median was considered abnormal. Women were categorised into 4 groups based on the indication for invasive prenatal diagnostic assessment: advanced maternal age (group I; n = 6179), increased risk of foetal NTDs (group II; n = 258), ultrasonographically confirmed foetal NTDs (group III; n = 55) or other indications (group IV; n = 1489). RESULTS: In group I, 18 of 6179 samples had increased AFP levels (0.3%), 2 of which were associated with NTDs. In group II, 2 of 258 samples had increased AFP levels (0.8%); both were associated with NTDs. Increased AFP levels were found in 44 of 55 samples from group III (80%), and 223 of 1489 samples from group IV (15.0%). CONCLUSION: Routine assessment of AFP in amniotic fluid based on advanced maternal age provides little additional value in the detection of NTDs beyond that of week 20 ultrasound.

Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23-q24.

Spinal muscular atrophies are a heterogeneous group of disorders. They differ in time of onset, clinical presentation, progression, severity and mode of inheritance. In 1985 a Dutch family was described with a dominant, non-progressive spinal muscular atrophy presenting at birth with arthrogryposis (MIM 600175). Linkage analysis was performed in this family. After having excluded the loci for Werdnig-Hoffmann's disease and for dominant distal spinal muscular atrophy with upper limb predominance, we were able to localise the gene to a 10 cM interval between the markers D12S78 and D12S1646 on chromosome 12q23-q24. Recently, dominant scapuloperoneal spinal muscular atrophy has been localised to an overlapping interval. However, the clinical appearances of scapuloperoneal spinal muscular atrophy and the present disorder make allelism unlikely. In 1994, a second Dutch family with a disorder similar to the present one was described. We excluded linkage to markers of the 12q23-q24 region in this family and thereby proved genetic heterogeneity of this type of dominant, congenital and nonprogressive spinal muscular atrophy.

Menstrual disorders and endocrine profiles in fragile X carriers prior to 40 years of age: a pilot study.

This prospective study reports serum hormone measurements associated with menopause in fragile X carriers (n = 9, age between 31-40 years). These results demonstrate the occurrence of premature ovarian failure.

Penetrance estimate of the fra(X) gene using Pointer versus direct estimate.

Direct estimate of the penetrance of the fra(X) gene was compared with the estimate using the Pointer computer program. Direct estimate gave overall penetrances of 85% for male and 64% for female carriers. The estimates calculated by the Pointer program were 82% for males and 38% for females. It is argued that the use of the Pointer program gives incorrect estimates of the penetrance of the fra(X) gene.

Validation of linkage-based DNA-diagnosis of fragile X gene carriers with the CGG repeat probe.

We have evaluated our carrier testing for the fragile X [fra(X)] syndrome, which was based on linked DNA markers, with the direct analysis of the CGG repeat sequence in the fra(X) gene. PstI and EcoRI blots were hybridized with a probe derived from the region just 3' of the CGG repeat in Xq27.3. We found the mutation analysis to be very sensitive as all 71 obligate gene carriers as well as 135 fra(X) patients tested showed evidence for an increased restriction fragment length encompassing the CGG repeat sequence with or without dispersion of the hybridization signal (mosaicism). Based on linked DNA markers, 6 out of 50 cytogenetic negative and mentally normal males at risk and 15 of 72 females at risk had inherited the allele at risk. All of these diagnoses could be confirmed by analysis of the CGG repeat length.

Penetrance of fra(X) gene: influence of grandparental origin of the gene, mental status of the carrier mother, and presence of a normal transmitting male.

Previous studies have indicated that the fragile X [fra(X)] gene does not show full penetrance (mental impairment) in carrier females or "carrier" males. The phenomenon of non-expressing carrier males distinguishes the fra(X) syndrome from all other known X-linked disorders. Moreover, penetrance of the fra(X) gene apparently does not show random distribution within fra(X) families, but seems to be reduced in sibs of normal transmitting males (NTM's). The availability of many large multigeneration fra(X) families, studied by cytogenetic and DNA analyses, enabled us to refine the estimates of the penetrance. From our data we conclude that the penetrance in daughters of carrier females is determined by the mental status of the mother. In sons of carrier females, the observed penetrance appears to be influenced by the grandparental origin of the gene as well as by the mental status of the mother. However, in contrast with the average penetrance, we observed a strongly reduced penetrance of the fra(X) gene in brothers (14%) and sisters (21%) of NTM's. These findings have profound implications for genetic counseling.

Familial X-linked mental retardation and isolated growth hormone deficiency: clinical and molecular findings.

We report on several members of a family with varying degrees of X-linked mental retardation (XLMR), isolated growth hormone deficiency (IGHD), and infantile behaviour but without other consistent phenotypic abnormalities. Male patients continued to grow until well into their twenties and reached a height ranging from 135 to 159 cm. Except one, all female carriers were mentally normal; their adult height ranged from 159 to 168 cm. By linkage studies we have assigned the underlying genetic defect to the Xq24-q27.3 region, with a maximum lod score of Z = 3.26 at theta = 0.0 for the DXS294 locus. The XLMR-IGHD phenotype in these patients may be due to pleiotropic effects of a single gene or it may represent a contiguous gene syndrome.

A gene for nonspecific X-linked mental retardation (MRX41) is located in the distal segment of Xq28.

We report on a family in which nonsyndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at theta = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at theta = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization.

Psychometric assessment of families with X-linked mental retardation.

As part of an integrated approach to DNA-linkage analysis in X-linked mental retardation (XLMR), 29 members of five families suspected of having XLMR underwent psychometric assessment. Mental retardation was confirmed in all participants. The range of mental retardation varied from mild to profound within and between families. In addition, these preliminary results indicated family-specific cognitive profiles in MRX45 and MRX46. The fact that two non-overlapping loci were involved provides strong evidence that specific cognitive profiles are linked to specific loci (genes) in mental retardation. We therefore recommend the application of standardised psychometric tests for the assessment of XLMR.

Characteristics of the transmission of the FMR1 gene from carrier females in a prospective sample of conceptuses.

The Prospective Study of the Fragile X Syndrome is a large collaborative effort designed to collect prospective data on the pregnancy outcomes of individuals who carry the fragile X mutation. The goal of this 5-year study is to obtain empiric recurrence risks and population parameters for the fragile X syndrome in order to characterize the underlying mechanism of the mutation and the factors that influence its expression. This report presents the DNA results on the first 152 cases of female carriers and their pregnancy outcomes. It was found that the sex ratio of conceptuses was not significantly different from 1.0 and was not associated with mutation status. Thus, there was no evidence for selection against zygotes with full mutations. There was a significant association between the form of the mutation in carrier mothers and the frequency of its transmission. Examination of the segregation ratios from premutation mothers showed that there was a deficit of conceptuses that received the fragile X mutation. The segregation ratio from full mutation carrier mothers did not differ from expected. Several explanations for this observation are discussed. Numbers of cases are too small to estimate recurrence risks; however, the general trend of the data confirm the association of recurrence risks and the repeat number carried by the mother.

Characterization of a highly polymorphic dinucleotide repeat 150 KB proximal to the fragile X site.

Fragile X [fra (X)] syndrome is a frequently encountered form of mental retardation and is inherited as an X-linked semi-dominant trait with reduced penetrance. We report here the characterization of a highly polymorphic dinucleotide repeat, DXS 548, which is approximately 150 kb proximal to the fra(X) site and the associated FMR-1 gene. DXS 548 is tightly linked to the fra (X) syndrome locus (FRAXA) without recombination (LOD = 9.07 with q of 0) in selected families with crossovers between FRAXA and very closely linked flanking markers. This dinucleotide repeat could be useful in determining the parental origin of a new fra (X) mutations and evaluating the role of FMR-1 in X-linked non-specific mental retardation.

Four families (MRX43, MRX44, MRX45, MRX52) with nonspecific X-linked mental retardation: clinical and psychometric data and results of linkage analysis.

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.

X-linked mental retardation: evidence for a recent mutation in a five-generation family (MRX65) linked to the pericentromeric region.

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.

[Perinatal asphyxia as incorrect explanation for mental retardation]. / 'Perinatale asfyxie' als onterechte verklaring voor mentale retardatie.

Three women, aged 21, 34 and 32 and with a family history of mental retardation said to be caused by perinatal asphyxia, each gave birth to a child with mental retardation. A chromosomal translocation, fragile X syndrome, and myotonic dystrophy could be diagnosed, respectively. In retrospect, the diagnosis of perinatal asphyxia in the family history had been too readily accepted. In reality the mental retardation was caused by a genetic disorder. Physicians are used to making a diagnosis, and when a diagnosis is not (yet) possible, they try to establish a working diagnosis or differential diagnosis. Too often such a working diagnosis becomes, through time, a definite diagnosis.

Incidental prenatal diagnosis of sex chromosome aneuploidies: health, behavior, and fertility.

Objective. To assess the diagnostic relevance of incidental prenatal findings of sex chromosome aneuploidies. Methods. We searched with medical subject headings (MeSHs) and keywords in Medline and the Cochrane Library and systematically screened publications on postnatally diagnosed sex chromosomal aneuploidies from 2006 to 2011 as well as publications on incidentally prenatally diagnosed sex chromosomal aneuploidies from 1980 to 2011. Results. Postnatally diagnosed sex chromosomal aneuploidies demonstrated three clinical relevant domains of abnormality: physical (22-100%), behavior (0-56%), and reproductive health (47-100%), while incidentally prenatally diagnosed sex chromosomal aneuploidies demonstrated, respectively, 0-33%, 0-40%, and 0-36%. Conclusion. In the literature incidental prenatal diagnosis of sex chromosomal aneuploidies is associated with normal to mildly affected phenotypes. This contrasts sharply with those of postnatally diagnosed sex chromosomal aneuploidies and highlights the importance of this ascertainment bias towards the prognostic value of diagnosis of fetal sex chromosomal aneuploidies. This observation should be taken into account, especially when considering excluding the sex chromosomes in invasive prenatal testing using Rapid Aneuploidy Detection.