Katelijne Bouman

The Introduction of Arrays in Prenatal Diagnosis : A Special Challenge

Genome‐wide arrays are rapidly replacing conventional karyotyping in postnatal cytogenetic diagnostics and there is a growing request for arrays in the prenatal setting. Several studies have documented 1–3% additional abnormal findings in prenatal diagnosis with arrays compared to conventional karyotyping. A recent meta‐analysis demonstrated that 5.2% extra diagnoses can be expected in fetuses with ultrasound abnormalities. However, no consensus exists as to whether the use of genome‐wide arrays should be restricted to pregnancies with ultrasound abnormalities, performed in all women undergoing invasive prenatal testing or offered to all pregnant women. Moreover, the interpretation of array results in the prenatal situation is challenging due to the large numbers of copy number variants with no major phenotypic effect. This also raises the question of what, or what not to report, for example, how to deal with unsolicited findings. These issues were discussed at a working group meeting that preceded the European Society of Human Genetics 2011 Conference in Amsterdam. This article is the result of this meeting and explores the introduction of genome‐wide arrays into routine prenatal diagnosis. We aim to give some general recommendations on how to develop practical guidelines that can be implemented in the local setting and that are consistent with the emerging international consensus. Hum Mutat 33:923–929, 2012.

A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype–phenotype correlations in type XI collagenopathies

A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1 mutations were found in 10 individuals. A splice site alteration (involving introns 47–55) was present in seven cases, with one in intron 50 (c.3816 + 1G > A) occurring in three patients. Two patients had a different deletion, and a missense mutation (Gly1471Asp) was observed in one case. In 4/10 patients the phenotype was classified as Marshall syndrome because of early‐onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50. One of these cases had a type 1 vitreous anomaly despite the presence of a COL11A1 mutation. The remaining 6/10 patients had an overlapping Marshall–Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50.

Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disease with a high mutation rate. It is clinically a very variable disorder and hamartomas can occur in many different organs. TSC shows genetic heterogeneity; one gene, TSC1, is on chromosome 9q34, and the second gene, TSC2, on chromosome 16p13.3. Clinical criteria for diagnosis have been established, but diagnosis of patients with minimal expression of the disease can be very difficult. In children the phenotype is often incomplete or not fully assessable. Hence mildly affected subjects, at risk for severely affected offspring, may remain undiagnosed. The detection of (small) mutations in the tuberous sclerosis gene located on chromosome 16 (TSC2) has recently become possible and may be helpful in the diagnosis of ambiguous cases. To our knowledge, this is the first report of a point mutation in the TSC2 gene in a familial case of tuberous sclerosis. A nonsense mutation was detected in a family in which the father had only minor signs hinting at tuberous sclerosis. The son had multiple cardiac tumours and white patches, but full clinical investigation was impossible in this child. This case illustrates that mutation analysis can contribute to a diagnosis of tuberous sclerosis in families with an incomplete phenotype.

Outcome of infants presenting with echogenic bowel in the second trimester of pregnancy

Objective Fetal echogenic bowel (FEB) is a soft marker found on second trimester sonography. Our main aim was to determine the outcome of infants who presented with FEB and secondarily to identify additional sonographic findings that might have clinical relevance for the prognosis. Design We reviewed all pregnancies in which the diagnosis FEB was made in our Fetal Medicine Unit during 2009–2010 (N=121). We divided all cases into five groups according to additional sonographic findings. Group 1 consisted of cases of isolated FEB, group 2 of FEB associated with dilated bowels, group 3 of FEB with one or two other soft markers, group 4 of FEB with major congenital anomalies or three or more other soft markers, and group 5 consisted of FEB with isolated intrauterine growth restriction (IUGR). Results Of 121 cases, five were lost to follow-up. Of the remaining 116 cases, 48 (41.4%) were assigned to group 1, 15 (12.9%) to group 2, 15 (12.9%) to group 3, 27 (23.2%) to group 4, and 11 (9.5%) to group 5. The outcome for group 1 was uneventful. In group 2 and 3, two anomalies, anorectal malformation and cystic fibrosis, were detected postnatally (6.7%). In group 4, mortality and morbidity were high (78% resp. 22%). Group 5 also had high mortality (82%) and major morbidity (18%). Conclusions If FEB occurs in isolation, it is a benign condition carrying a favourable prognosis. If multiple additional anomalies or early IUGR are observed, the prognosis tends to be less favourable to extremely poor.

The implementation of unit-based perinatal mortality audit in perinatal cooperation units in the northern region of the Netherlands

BackgroundPerinatal (mortality) audit can be considered to be a way to improve the careprocess for all pregnant women and their newborns by creating an opportunity to learn from unwanted events in the care process. In unit-based perinatal audit, the caregivers involved in cases that result in mortality are usually part of the audit group. This makes such an audit a delicate matter.MethodsThe purpose of this study was to implement unit-based perinatal mortality audit in all 15 perinatal cooperation units in the northern region of the Netherlands between September 2007 and March 2010. These units consist of hospital-based and independent community-based perinatal caregivers. The implementation strategy encompassed an information plan, an organization plan, and a training plan. The main outcomes are the number of participating perinatal cooperation units at the end of the project, the identified substandard factors (SSF), the actions to improve care, and the opinions of the participants.ResultsThe perinatal mortality audit was implemented in all 15 perinatal cooperation units. 677 different caregivers analyzed 112 cases of perinatal mortality and identified 163 substandard factors. In 31% of cases the guidelines were not followed and in 23% care was not according to normal practice. In 28% of cases, the documentation was not in order, while in 13% of cases the communication between caregivers was insufficient. 442 actions to improve care were reported for ‘external cooperation’ (15%), ‘internal cooperation’ (17%), ‘practice organization’ (26%), ‘training and education’ (10%), and ‘medical performance’ (27%). Valued aspects of the audit meetings were: the multidisciplinary character (13%), the collective and non-judgmental search for substandard factors (21%), the perception of safety (13%), the motivation to reflect on one’s own professional performance (5%), and the inherent postgraduate education (10%).ConclusionFollowing our implementation strategy, the perinatal mortality audit has been successfully implemented in all 15 perinatal cooperation units. An important feature was our emphasis on the delicate character of the caregivers evaluating the care they provided. However, the actual implementation of the proposed actions for improving care is still a point of concern.

Perinatal death investigations: What is current practice?

Abstract Perinatal death (PD) is a devastating obstetric complication. Determination of cause of death helps in understanding why and how it occurs, and it is an indispensable aid to parents wanting to understand why their baby died and to determine the recurrence risk and management in subsequent pregnancy. Consequently, a perinatal death requires adequate diagnostic investigation. An important first step in the analysis of PD is to identify the case circumstances, including relevant details regarding maternal history, obstetric history and current pregnancy (complications are evaluated and recorded). In the next step, placental examination is suggested in all cases, together with molecular cytogenetic evaluation and fetal autopsy. Investigation for fetal–maternal hemorrhage by Kleihauer is also recommended as standard. In cases where parents do not consent to autopsy, alternative approaches such as minimally invasive postmortem examination, postmortem magnetic resonance imaging, and fetal photographs are good alternatives. After all investigations have been performed it is important to combine findings from the clinical review and investigations together, to identify the most probable cause of death and counsel the parents regarding their loss.

Stillbirth and neonatal mortality in pregnancies complicated by major congenital anomalies: Findings from a large European cohort

To provide prognostic information to help parents to reach an informed decision about termination or continuation of the pregnancy and to shape peripartum policy based on a large European cohort.

NIPTRIC : an online tool for clinical interpretation of non-invasive prenatal testing (NIPT) results

To properly interpret the result of a pregnant woman’s non-invasive prenatal test (NIPT), her a priori risk must be taken into account in order to obtain her personalised a posteriori risk (PPR), which more accurately expresses her true likelihood of carrying a foetus with trisomy. Our aim was to develop a tool for laboratories and clinicians to calculate easily the PPR for genome-wide NIPT results, using diploid samples as a control group. The tool takes the a priori risk and Z-score into account. Foetal DNA percentage and coefficient of variation can be given default settings, but actual values should be used if known. We tested the tool on 209 samples from pregnant women undergoing NIPT. For Z-scores < 5, the PPR is considerably higher at a high a priori risk than at a low a priori risk, for NIPT results with the same Z-score, foetal DNA percentage and coefficient of variation. However, the PPR is effectively independent under all conditions for Z-scores above 6. A high PPR for low a priori risks can only be reached at Z-scores > 5. Our online tool can assist clinicians in understanding NIPT results and conveying their true clinical implication to pregnant women, because the PPR is crucial for individual counselling and decision-making.

Risk of erroneous results in carrier testing for haemophilia A without prior DNA analysis in male index patients

D. E. FRANSEN VAN DE PUTTE,* W. S. FRANKHUIZEN,* L. VIJFHUIZEN,* L. GROENEWEGEN,* R. Y. J . TAMMINGA,† K. BOUMAN,‡ A. J . VAN ESSEN,‡ A. C. J . GIJSBERS,* C. A. L. RUIVENKAMP* and E. M. J . BOON* *Department of Clinical Genetics, Leiden University Medical Center, Leiden; †University Medical Center Groningen, Beatrix Children’s Hospital; and ‡Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

OP18.07: Pre‐ and postnatal diagnosis of fetal trisomy in the north‐east of the Netherlands

Objectives: To describe the diagnostic pathway for 175 consecutive cases of trisomy 21, 18 or 13. Methods: Prenatal and postnatal data were examined from 118 consecutive cases of trisomy 21 and 57 cases of trisomy 18 or trisomy 13 with an estimated date of delivery was between 1-6-2008 and 1-6-2010. Results: In 73 (42%) of 175 trisomic pregnancies a first trimester (FTS) scan was performed and in 62 (85%) of these cases an anomaly was diagnosed or the risk of the combined test was increased. In 61 (35%) trisomic pregnancies FTS was declined but a second trimester scan (STS) was performed which revealed anomalies in 38% of cases with trisomy 21 and a 83% with trisomy 18 or 13. In 18 (10%) of the affected pregnancies neither invasive testing nor FTS or STS were performed. Conclusions: The first trimester scan (FTS) and the combined test (CT) are effective in detecting fetal trisomy. If screening is postponed to the second trimester the detection of trisomy 21 is less than 50%; fetuses with trisomy 18 or 13 are almost always identified but not always before the legal limit for abortion.