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Myotonic dystrophy (DM) or Steinert's disease is a progressive autosomal dominant disease characterized by increasing muscle weakness, myotonia, cataracts, and endocrine abnormalities such as diabetes and testicular atrophy. The gene for DM was cloned in 1992 and the mutation was shown to be an expanded trinucleotide (CTG) repeat. A polymerase chain reaction (PCR)-based assay was described soon after that would allow (prenatal) diagnosis of the disease. Based on these PCR assays, we have developed a method for carrying out single-cell PCR for DM. In preimplantation diagnosis, embryos obtained in vitro are checked for the presence or absence of a disease, after which only embryos shown to be free of the disease under consideration are returned to the mother. A single-cell assay was developed for preimplantation diagnosis in couples where one of the parents is afflicted with DM. Twenty intracytoplasmic sperm injection (ICSI) cycles were carried out in eight patients and between one and four embryos were replaced in 17 out of 20 cycles. Two of the patients became pregnant and have had prenatal diagnosis which has confirmed that they are unaffected.

Isolated congenital long QT syndrome is an autosomal dominant disorder characterized by recurrent syncopes, ventricular arrhythmias, or sudden death often accompanied by a prolonged QTc interval on ECG. On the occasion of a pregnancy complicated by an intra-uterine death of a full term baby with prolonged bradycardia a long QT syndrome was diagnosed in the mother. Familial examination revealed a prolonged QTc in her mother, brother and sister, all with positive history of syncopes. DNA linkage analysis was subsequently performed in this family with DNA markers on the short arm of chromosome 11. Four of the children in the family, younger than 5 years, were found to be asymptomatic carriers. Three of them showed a clear QTc prolongation on a 12 lead ECG. Another showed QTc prolongation during Holter monitoring but had a normal basic ECG. Measurement of QTc interval in families affected by the long QT syndrome is helpful but does not always permit an accurate diagnosis. Familial screening with DNA linkage analysis especially in families where a member is affected by the syndrome, can reveal "masked" cases which can further be investigated with Holter or effort ECG. The identification of locus heterogeneity of the long QT syndrome complicates genetic diagnosis. Only prospective studies in more families with long QT syndrome can show the additional diagnostic and prognostic value of DNA linkage.

BACKGROUND: Preimplantation genetic diagnosis (PGD) and subsequently preimplantation genetic screening (PGS) have been introduced since I990. The difference from the already existing in vitro fertilization (IVF) technology, using intracytoplasmic sperm injection (ICSI), was the embryo biopsy at day 3 after fertilization. Although healthy children post-PGD/PGS have been born, the question of whether embryo biopsy could have any harmful effects has to be studied on large series in a prospective manner. METHODS: A prospective cohort study was undertaken from I992 until 2005, using the same approach as for the follow-up of IVF and ICSI children conceived in the same centre. Questionnaires were sent to physicians and parents at conception and at delivery. Children were examined at 2 months of age by trained clinical geneticists whenever possible. RESULTS: Data collected on 58I post-PGD/PGS children showed that term, birthweight and major malformation rates were not statistically different from that of 2889 ICSI children, with overall rates of major malformation among these post-PGD/PGS and ICSI children being 2.I3 and 3.38%, respectively (odds ratio [OR]: 0.62; exact 95% confidence limits [95% CL]: 0.31 - 1.15). However, the overall perinatal death rate was significantly higher among post-PGD/PGS children compared with ICSI children (4.64 versus I.87%; OR: 2.56; 95% CL: I.54―4.I8). When stratified for multiple births, perinatal death rates among PGD/PGS singleton and ICSI singleton children were similar (I.03 versus I.30%; OR: 0.83; 95% CL: 0.28―2.44), but significantly more perinatal deaths were seen in post-PGD/PGS multiple pregnancies compared with ICSI multiple pregnancies (II.73 versus 2.54%; OR: 5.09; 95% CL: 2.80-9.90). The overall misdiagnosis rate was below I%. CONCLUSIONS: Embryo biopsy does not add risk factors to the health of singleton children born after PGD or PGS. The perinatal death rate in multiple pregnancies is such that both caution and long-term follow-up are required.

background: Outcome data on children born after assisted reproduction treatments are important for both patients and health-care providers. The objective of this study was to determine whether embryo biopsy as performed in PGD has an impact on the health of infants up to 2 months of age. methods: A prospective comparative follow-up study of children born after PGD and children born after ICSI by collecting written reports and performing a physical examination at 2 months was performed. Auxological data at birth and physical findings up to 2 months of age were compared for 995 children consecutively live born after embryo biopsy (1994 –2009) and for a control group of 1507 children born after ICSI with embryo transfer on Day 5. results: No differences regarding mean term, prematurity (term ,32 w and ,37 w), mean birthweight, very low birthweight (,1500 g), perinatal death, major malformations and neonatal hospitalizations in singletons and multiples born following PGD versus ICSI were observed. Compared with ICSI, fewer multiples born following PGD presented a low birthweight (,2500 g) (P ¼ 0.005). conclusions: Embryo biopsy for PGD does not introduce extra risk to the overall medical condition of newborn children. Multiples born following embryo biopsy appear to be at lower risk for low birthweight compared with multiples born following ICSI.

Background The objective of this study was to assess socio-emotional and language development in 2-year-old children born after preimplantation genetic diagnosis (PGD) and genetic aneuploidy screening (PGS), intracytoplasmic sperm injection (ICSI) and natural conception (NC) and to assess parental well-being. Methods Parents of 2-year-old PGD/PGS (n = 41), ICSI (n = 35) and NC (n = 53) singleton children were recruited. The socio-emotional development of the children was assessed using the Child Behavioural Checklist (CBCL) and the Short Temperament Scale for Toddlers. Parental stress and health status was measured with the Parent Stress Index and the General Health Questionnaire. Language development was assessed with the McArthur Communicative Development Inventories. Results No differences were found for temperament, language development, parental stress or health status. The mothers in the PGD/PGS and ICSI group reported significantly fewer CBCL Total problems than their NC counterparts, whereas for the CBCL Externalizing problems, only the ICSI mothers reported fewer problems than their PGD/PGS and NC counterparts. Fathers in the ICSI group also rated their children as having fewer Externalizing and Total behavioural problems. Conclusions PGD/PGS conception does not adversely affect children's socio-emotional and language development at age 2, nor did parents differ from ICSI and NC parents for parental stress and health status.

Introduction: In preimplantation genetic diagnosis (PGD) or preimplantation genetic screening (PGS), embryo biopsy is an invasive essential procedure. The major objective of this study was to determine if the embryo biopsy might affect health outcome of children. The applied biopsy technique through aspiration of 1 or 2 blastomeres was the same in all PGD/PGS conceptions. A control group of children born after intracytoplasmic sperm injection (ICSI) with embryo transfer on day 5, similarly to the procedure after PGD/PGS was included, to determine whether potential differences in children's outcome could be exclusively attributed to the embryo biopsy. Data on outcome at birth are reported here. Materials and Methods: A prospective longitudinal follow-up study on medical outcome of all children born after embryo biopsy at the Centre for Reproductive Medicine of the UZ Brussel has been undertaken since 1993 using the same protocol as for the follow-up of children born after ICSI in the same centre. Data on pregnancy and birth were obtained through written questionnaires. The children were examined and checked for possible major anomalies at 2 months of age by trained clinical geneticists whenever possible. Malformations were classified according to criteria previously defined at our centre. A major malformation causes functional impairment and/or requires surgical correction. Mean term, birthweight, major malformations, perinatal death and the number of neonatal hospitalizations were compared for both groups. Statistical analysis included the Fisher's exact test for comparison. Results: Data on medical outcome of 995 children (670 singletons, 308 twins and 17 triplets) born after PGD/PGS were compared with 1507 children (1059 singletons, 433 twins and 15 triplets) conceived after intracytoplasmic sperm injection (ICSI) at our centre between 1993 and December 2008. No statistically significant differences regarding mean term, prematurity (term

Introduction Embryo biopsy is a new invasive procedure applied in ART for diagnostic reasons in Preimplantation Genetic Diagnosis (PGD) or to increase pregnancy rate in Aneuploidy screening (PGS). Along with every new application in ART questions arise on the psychological development of the resulting offspring and parental wellbeing. The objective of this ongoing study is to investigate temperament, behavioural-emotional and language development in 2,5 year old children born after PGD/PGS, Intracytoplasmic Sperm Injection (ICSI) and natural conception (NC) and to assess the health status and parenting stress of their respective parents. Materials and Method Parents of PGD/ PGS (n = 36) and ICSI (n = 41) children were recruited from the registry of the Universitair Ziekenhuis Brussel. Parents of NC children (n = 31) were recruited from day-care centres. Parents in all 3 conception groups were asked to fill out a number of questionnaires when their child was between 24 and 32 months of age with the PGD/PGS children being slightly, although significantly younger, than the ICSI and NC children (PGD/PGS: 26.88 months, ICSI: 28.18 months, NC: 28.48 months; F (2, 117) = 6.37, p 0.05), sex (p > 0.05) and birth order (p > 0.05). Data on interval level were analysed using ANOVA s with conception mode as fixed factor and test scores on CBCL, N-CDI, PSI and GHQ as dependent variables. A significance level of 0.05 was accepted. When significance was obtained a Post Hoc Sheffé test was carried out. Results from the STST on nominal level were analysed using a Chi Square test. Results When comparing mothers as well as fathers in the three conception groups we observed no significant differences in the amount of internal behavioural-emotional problems (mothers: F(2.66) = 0.066; p = 0.936; fathers: F(2.53) = 0.592; p = 0.557) or external behavioural-emotional problems (mothers: F(2.66) = 0.233; p = 0.793; fathers: F (2.53) = 0.107; p = 0.898) reported. Also, no differences were found between PGD, ICSI and NC mothers (p > 0,05) and fathers (p > 0,05) in their perception of their child s temperament. According to either mothers or fathers the production of words (F (2.55) = 2.101; p = 0.132) and understanding of words (F (2.55) = 0.063; p = 0.939) develops equally between PGD/PGS, ICSI and NC children. Parents in all three conception groups experienced an equal amount of stress from parenting (mothers: F (2.67) = 1.069; p = 0.349, fathers: F (2.54) = 0.343; p = 0.711) and reported an equal health status (GHQ) (mothers: F (2.65) = 0.007; p = 0.993; fathers: F (2.52) = 0.064; p = 0.938). Conclusion These preliminary results point out that there are no differences in language development, temperament and behavioural-emotional development between children born after PGD/PGS, ICSI or natural conception as reported by their parents. Moreover, parents of PGD/PGS, ICSI and natural conceived children experience an equal amount of parenting stress and have a comparable health status. Although these results are very reassuring we currently are assessing a larger sample in order to confirm these findings.

BACKGROUND: Embryo biopsy is an essential but invasive procedure to perform preimplantation genetic diagnosis (PGD) or preimplantation genetic screening (PGS). The major objective of this study was to determine whether embryo biopsy might cause post-natal growth restriction. METHODS: We compared growth data and physical findings at birth and 2 years for singletons born either after PGD/PGS (n = 70), ICSI (n = 70) or natural conception (NC) (n = 70). Children were matched for gender, maternal educational level, mother tongue and birth order. RESULTS: No significant differences were found between the three groups regarding weight, height and head circumference standard deviation scores (SDS) at birth and at age 2 years, although the PGD/PGS children tended to have a lower birthweight compared with the NC children. At 2 years, the mean BMI SDS in PGD/PGS children was significantly lower compared with NC children (P = 0.005). PGD/PGS children were more frequently born after Caesarian section than ICSI children, but had no more congenital malformations, hospital admissions and surgical interventions compared with ICSI and NC children. CONCLUSIONS: Singleton children at age 2 years born after embryo biopsy applied in PGD/PGS present a similar post-natal linear growth compared with ICSI and NC children. PGD/PGS singletons appear not to be at higher risk for congenital malformations and surgical interventions during the first 2 years of life. To date, there have been no observable detrimental effects of the PGD/PGS procedure on children. © The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

The clinical phenotype of cystic fibrosis (CF) patients is very variable and it has been suggested that patients lacking the cystic fibrosis transmembrane conductance regularor(CFTR) have milder lung disease than those having an altered CFTR. However, on the basis of the large variation in lung function in patients homozygous for the most common CF mutation, deltaF508, and W1282X homozygotes, it was concluded that most CF patients have a common phenotype, but that other genetic and environmental factors may be important for the clinical phenotype. We describe a patient, homozygous for a frameshift mutation in the regulatory (R)domain of the CFTR, who presented with mild lung disease but severe hepatic and pancreatic involvement. The mutation, 2184delA (deletion of A at position 2184 together with an A to G substitution atposition 2183 in exon 13) was originally characterised by D Bozon and L-C Tsui (personal communication) and was found in both parents of our patient in a screening programme of non-deltaF508 CF chromosomes with denaturing gradient gel electrophoresis, followed by sequencing. The boy was born at term in December 1977, birth weight 3500g, to healthy, nonconsanguineous parents. Cystic fibrosis presented neonatally with meconium ileus which was treated surgically. CF was confirmed by positive pilocarpine iontophoresis sweat test at 10 days. Conventional treatment for CF was given. The clinical course of the lung disease was mild. At the age of 5 years a nasal polypectomy was performed. Liver function tests altered from this age onwards. Hepatomegaly was observed two years later. He was admitted to hospital at the age of 11,5 years for intravenous antibiotic treatment because of pulmonary infection. Pseudomonas aeruginosa was isolated from sputum cultures soon after this, but not repeatedly. At 13,5 years he was asymptomatic with discrete clubbing, hepatomegaly of 4 cm, and pubertal state A1P1G2. Weight and height were between the 10th and 25th centiles. Respiratory function tests for FVC, FEV, and PEFR were 89%, 83%, and 76% of predicted, respectively. Schachman score was good (80/100) as was the Chrispin-Norman score at 6/38. ALT (71 IU/l, normal

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis for patients at risk of transmitting an inherited disease such as myotonic dystrophy type 1(DM1) to their offspring. In this paper, the clinical application of preimplantation diagnosis for DM1 upon request to children born is described in a large cohort of risk couples. PGD could be offered to all 78 couples opting for PGD regardless of the triplet repeat size. The incidence of major complications was minimalised following a careful assessment in affected DM1 females anticipating possible cardiological, obstetrical and anaesthetical problems. A live-birth delivery rate per cycle with oocyte retrieval of 20% was the outcome. Forty-eight of the 49 children born are in good health and have normal psychomotor development.