Implications For Prenatal Diagnosis Research Articles

Whole Exome Sequencing (WES) enhances the diagnostic rate of perinatal autopsy: A prospective clinical utility trial with implications for prenatal diagnosis

Genomic classification is rapidly becoming a routine and integral part of diagnosis in pathology. Perinatal pathology is following this trend. The aims of this study were to determine the utility of WES in perinatal autopsy for congenital anomalies and to model the outcome of WES as a prenatal test. A total of 131 probands with congenital anomalies who underwent post mortem examination were referred by pathologists to the study. 82 probands were considered suitable for sequencing. The parents of 5 declined enrolment and 10 could not be consented. 67 probands were enrolled. Autopsy identified specific diagnoses in 11 cases (17%). WES identified specific diagnoses (‘pathogenic’ or ‘likely pathogenic’ variants) in 23 cases – a diagnostic rate of 35%. The combined diagnostic rate of autopsy and sequencing was 38%. A geneticist blinded to the autopsy findings reviewed the probands’ antenatal imaging reports and recommended a gene list to model the clinical utility of prenatal WES. The use of antenatal sequencing in this cohort would have identified a specific diagnosis in 18 of the 23 cases with positive sequencing findings. In conclusion, WES doubles the diagnostic rate of autopsy for congenital anomalies and our data supports the prenatal use of genomic sequencing.

Hb D-Punjab in Punjab Province, Pakistan and Its Implications for Prenatal Diagnosis: Experience at the Punjab Thalassemia Prevention Program (PTPP)

The Hb D-Punjab (HBB: c.364C>G) hemoglobinopathy is an asymptomatic disorder in heterozygotes as well as homozygotes. It is mostly seen in approximately 1.0% of the Punjabis. It is known to cause s...

FOXN1 Italian founder mutation in Indian family: Implications in prenatal diagnosis

The Forkhead box N1 (FOXN1) is a transcriptional factor regulating the development, differentiation and function of thymic epithelial cells; maintaining T-lineage progenitors in bone marrow; promoting terminal differentiation of epithelial cells of hair follicles. Mutation in FOXN1 was reported to cause a rare disorder characterized by rudimentary thymus gland, T-cell immunodeficiency, congenital alopecia and nail dystrophy within an Italian community. This is the first report of FOXN1 p.R255X mutation from India, outside this endogamous Italian community. Out of the two affected children, only one was alive during the genetic evaluation and had all the clinical manifestations such as alopecia totalis and nail dystrophy. The proband was homozygous for FOXN1 p.R255X Italian founder mutation. The carrier status of both the parents was established. Immunological study of the proband revealed total absence of T-cells confirming T-cell immunodeficiency. Prenatal diagnosis during third pregnancy revealed absence of FOXN1 mutation. To conclude, this is the first report of FOXN1 mutation from India highlighting that diseases once confined to certain geographical areas are spreading across the globe probably due to human migrations.

Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia.

Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and SNP arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis.

Coinheritance of Hb D-Punjab and β-Thalassemia: Diagnosis and Implications in Prenatal Diagnosis

Hb D-Punjab (HBB: c.364G>C) is an abnormal hemoglobin (Hb) associated with genetic risk in association with Hb S (HBB: c.20A>T). In addition, misdiagnosing homozygosis for hemizygosis may have implication for genetic risk assessment. We present the diagnostic utility of high performance liquid chromatography (HPLC) in differential diagnosis between the Hb D-Punjab homozygote and the Hb D-Punjab/β-thalassemia (β-thal) genotype. The Hb A2 level measurement may not be a reliable parameter to differentiate between the two conditions. In a screening program for risk prediction, the genotype should be confirmed by family study and/or molecular analysis. Misdiagnosis can have potentially adverse implications in a prenatal diagnosis (PND) program, particularly in areas where consanguinity is common and this Hb D-Punjab variant occurs.

Prenatal unilateral cerebellar hypoplasia in a series of 26 cases: significance and implications for prenatal diagnosis

To define imaging patterns of unilateral cerebellar hypoplasia (UCH), discuss possible pathophysiological mechanisms and underline the etiology and prognosis associated with these lesions. In this retrospective study we reviewed the charts of 26 fetuses diagnosed between 2003 and 2011 with UCH, defined by asymmetrical cerebellar hemispheres with or without decreased transverse cerebellar diameter. The review included analysis of the anatomy of the cerebellar hemispheres, including foliation, borders and parenchymal echogenicity, and of the severity of the hypoplasia. Data from clinical and biological work-up and follow-up were obtained. Our series could be divided into two groups according to whether imaging features changed progressively or remained constant during follow-up. In Group 1 (n = 8), the progression of imaging features, echogenic cerebellar changes and/or hyposignal in T2*-weighted MR images were highly suggestive of ischemic/hemorrhagic insult. In Group 2 (n = 18), imaging features remained constant during follow-up; UCH was associated with abnormal foliation in three proven cases of clastic lesions, a cystic lesion was noted in three cases of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac abnormalities/aortic coarctation, eye abnormalities) syndrome and, in the remaining cases, UCH remained unchanged, with no imaging pattern typical of hemorrhage. In 24 cases the infant was liveborn and follow-up was continued in 23, for a mean period of 3 years. Among these, neurological complications were identified in seven (in one of seven (at a mean of 46 months) in Group 1 and in six of 16 (at a mean of 35 months) in Group 2). The surface loss of cerebellar hemisphere was > 50% in 19/24 fetuses and the vermis was clearly normal in appearance in 19/24. Predisposing factors for fetal vascular insult were identified in eight cases: these included maternal alcohol addiction, diabetes mellitus, congenital cytomegalovirus infection and pathological placenta with thrombotic vasculopathy and infarctions. UCH is defined as a focal lesion of the cerebellum that may be secondary to hemorrhage and/or ischemic insult, suggesting a clastic origin, particularly when imaging follow-up reveals changes over time. UCH may also be a clue for the prenatal diagnosis of PHACE syndrome. The amount of surface loss of cerebellar hemisphere does not correlate with poor prognosis. UCH with normal vermis is often associated with normal outcome.

Chromosomal Mosaicism in Human Feto-Placental Development: Implications for Prenatal Diagnosis.

Chromosomal mosaicism is one of the primary interpretative issues in prenatal diagnosis. In this review, the mechanisms underlying feto-placental chromosomal mosaicism are presented. Based on the substantial retrospective diagnostic experience with chorionic villi samples (CVS) of a prenatal diagnosis laboratory the following items are discussed: (i) The frequency of the different types of mosaicism (confined placental, CPM, and true fetal mosaicisms, TFM); (ii) The risk of fetal confirmation after the detection of a mosaic in CVS stratified by chromosome abnormality and placental tissue involvement; (iii) The frequency of uniparental disomy for imprinted chromosomes associated with CPM; (iv) The incidence of false-positive and false-negative results in CVS samples analyzed by only (semi-)direct preparation or long term culture; and (v) The implications of the presence of a feto-placental mosaicism for microarray analysis of CVS and non-invasive prenatal screening (NIPS).

Masking of a β-Thalassemia Determinant by a Novel δ-Globin Gene Defect [Hb A2-Saurashtra or δ100(G2)Pro→Ser; HBD: c.301C>T] in Cis

The molecular basis of β-thalassemia (β-thal) syndromes have been well documented, while the spectrum of mutations causing δ-thalassemia (δ-thal) has not been well characterized. δ-Thalassemia has no clinical symptoms but its coinheritance with heterozygous β-thal may cause misdiagnosis, especially in countries with a high prevalence of β-thal where prevention programs have been implemented. The coinheritance of β- and δ-globin mutations in India is not common. This association may interfere with correct diagnosis and genetic counseling of β-thal in screening programs. Here we report two families showing borderline Hb A2 levels belonging to the Koli Community, indigenous to the Saurashtra Province of Gujarat, India. They were referred to us for thalassemia molecular screening as they had children clinically presenting before 2 years of age and requiring regular blood transfusions. Interestingly, both families carried a novel δ-globin gene mutation at codon 100 (C>T) linked to a polyadenylation (polyA) site [AATAAA>A(–AATAA)] 5 bp deletional β-thal mutation, never before reported in the Indian population. This report highlights the importance of considering δ-globin gene analysis during β-thal screening to avoid false-negative results in the detection of at-risk couples. It also highlights how incomplete diagnosis of a borderline or normal Hb A2 level may lead to the probable birth of a β-thal major (β-TM) child. This has important implications in prenatal diagnosis.

Muscle MRI in female carriers of dystrophinopathy

Duchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy. Evaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed. We found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness. The pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.

First trimester sonographic dating formula for the Nigerian obstetric population

Objective: The main purpose of this study is to derive a dating formula for the Nigerian obstetric population, quantify its prediction error, and compare its performance with existing published formulae. Materials and Methods: The crown-rump length (CRL) of 322 fetuses without risk for fetal growth restriction were plotted against menstrual age to obtain a scatter plot from which we derived the best-fit fractional polynomial regression model for estimating gestational age (GA). The accuracy of the formula was compared with that of existing formula in another data set of 88 fetuses. Results: The scatter plot yielded a best-fit equation for the estimation of GA (in weeks) from CRL (in mm) as GA=−0.0008 (CRL2) + 0.168 CRL + 5.397, (R2=0.8017). The mean prediction error was 0.13 for our formula, and 0.16 and 0.20 for Nelson's, and Robinson's formulae, respectively. Conclusion: Our dating formula locally derived was more favorably applicable for the Nigerian population. This has implication for prenatal diagnosis in Nigeria.

Implications of prenatal diagnosis of the fetus with both interstitial deletion and a small marker ring originating from chromosome 5

We describe a patient with 47,XY,del(5)(p11p13), +mar observed in prenatal screening. We performed analyses including G-banding, multi-color fluorescent in situ hybridization (mFISH) for fetal chromosome detection. After birth array-based comparative genomic hybridization (aCGH), bacterial artificial chromosome (BAC)-FISH was carried out to define the chromosomal changes precisely. The mFISH revealed that a ring chromosome that had originated from chromosome 5. The aCGH showed that this fetus had a terminal duplication, an interstitial deletion, and a pericentromeric duplication of the short arm of chromosome 5. This complex alteration resulted in partial trisomy 5p15.33-p15.31, partial monosomy 5p14.3-p13.2, and partial trisomy 5p12-p11. To clarify these alterations, we performed BAC-FISH using BAC clones related to deleted and duplicated regions, and found that a derivative (der) chromosome 5 showed the presence of hybridization signals from the duplicated region at 5p15.33 and the loss of hybridization signals from the deleted region at 5p14.2. In addition, FISH analysis confirmed the origin of the marker chromosome. Hybridization signals from the second intervening sequence at 5p13.1, between the deleted region and the pericentric duplicated region, were present on the marker ring chromosome.

Advances in fetal therapy

Key content Fetal medicine is a rapidly developing subspecialty. The mainstay of treatment for fetal alloimmune thrombocytopenia remains maternal immunoglobulin therapy. Stem cell transplantation and gene therapy have advanced over the last decade but must still be considered experimental. Laser coagulation is the best treatment for all stages of twin‐to‐twin transfusion syndrome presenting before 26 weeks of gestation. Fetoscopic endoluminal tracheal occlusion appears to improve prognosis in severe congenital diaphragmatic hernia. Learning objectives To gain an overview of the recent developments in fetal therapy. To understand the benefits and risks of different methods of fetal therapy. To appreciate the importance of high‐quality research in fetal medicine. Ethical issues With the option of fetal therapy, the value and implications of prenatal diagnosis have to be reviewed. The acceptability of fetal therapy to parents and to society should be investigated. The consideration of the mother and fetus as individual people presents an inherent difficulty in implementing randomised controlled trials in fetal medicine. Please cite this article as: Morris RK, Chan BC, Kilby MD. Advances in fetal therapy. The Obstetrician & Gynaecologist 2010;12:94–102.

Congenital malformations after assisted reproduction: risks and implications for prenatal diagnosis and fetal medicine

Congenital malformations after assisted reproduction: risks and implications for prenatal diagnosis and fetal medicine

Critical Issues in Craniofacial Care: Quality of Life, Costs of Care, and Implications of Prenatal Diagnosis

Since the 2000 Surgeon General's Report on Oral Health (SGROH), substantial areas of inquiry relative to individuals, especially children and youth, with orofacial clefts and other craniofacial conditions have emerged. These areas include access to and cost of care, stigmatization and quality of life, and social and ethical issues around prenatal diagnosis. This update on the 2000 SGROH examines what we have learned about the cost and ability to access cleft and craniofacial care, prenatal diagnosis, and how quality of life is impacted by these conditions and the burden of care. The development of new research tools to assess quality of life since 2000 will permit further study of the impact of oral and craniofacial conditions on children and families and the effect of treatment on quality of life. Despite a better understanding of the higher use of services and increased costs of care for families of children with craniofacial conditions, major gaps in research must be addressed to assist with program planning and policy development for these groups of children and their families. Further work is also needed to assess the cost-effectiveness of craniofacial team care and to better understand family experience with accessing needed care. Finally, prenatal detection and diagnosis of clefts and craniofacial conditions have advanced dramatically, and the roles of craniofacial professionals and teams have been affected. New understandings of prenatal diagnosis and genomic sciences are redefining genetic counseling, therapy, and future preventive initiatives.

Multiple De Novo Mutations in the MECP2 Gene

Rett syndrome is an X-linked dominant disorder that usually arises following a single de novo mutation in the MECP2 gene. Point mutation testing and gene dosage analysis of a cohort of British Rett syndrome patients in our laboratory revealed four females who each had two different de novo causative mutations, presumed to be in cis because the patients showed no deviation from the classical Rett syndrome phenotype. Two of these cases had a point mutation and a small intraexonic deletion, a third had a whole exon deletion and a separate small intraexonic deletion, and a fourth case had a small intraexonic deletion and a large duplication. These findings highlight the necessity to perform both point mutation analysis and exon dosage analysis in such cases, particularly because of the possibility of undetected parental mosaicism and the implications for prenatal diagnosis in future pregnancies. These cases also suggest that the MECP2 gene may be particularly prone to multiple mutation events.

Retrospective detection of transaldolase deficiency in amniotic fluid: implications for prenatal diagnosis

Retrospective detection of transaldolase deficiency in amniotic fluid: implications for prenatal diagnosis

Novel and recurring ABCA12 mutations associated with harlequin ichthyosis: implications for prenatal diagnosis

Novel and recurring ABCA12 mutations associated with harlequin ichthyosis : implications for prenatal diagnosis

Variable penetrance of COL6A1 null mutations: Implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families

Collagen VI mutations cause mild Bethlem myopathy and severe, progressive Ullrich congenital muscular dystrophy (UCMD). We identified a novel homozygous COL6A1 premature termination mutation in a UCMD patient that causes nonsense-mediated mRNA decay. Collagen VI microfibrils cannot be detected in muscle or fibroblasts. The parents are heterozygous carriers of the mutation and their fibroblasts produce reduced amounts of collagen VI. The molecular findings in the parents are analogous to those reported for a heterozygous COL6A1 premature termination mutation that causes Bethlem myopathy. However, the parents of our UCMD proband are clinically normal. The proband’s brother, also a carrier, has clinical features consistent with a mild collagen VI phenotype. Following a request for prenatal diagnosis in a subsequent pregnancy we found the fetus was a heterozygous carrier indicating that it would not be affected with severe UCMD. COL6A1 premature termination mutations exhibit variable penetrance necessitating a cautious approach to genetic counselling.

Euchromatic variant 16p+. Implications in prenatal diagnosis

Euchromatic imbalances at the cytogenetic level are usually associated with phenotypic consequences. Among the exceptions are euchromatic variants of chromosome 16 (16p+) with normal phenotype. There is a growing list of euchromatic duplications and deletions involving both G-positive and G-negative bands that seem to be phenotypically neutral, but these euchromatic variants are rare. The aim of this report is to describe a new familial case of euchromatic variant 16p+ and to emphasise the misinterpretation of these rare euchromatic variants particularly when ascertained at prenatal diagnosis. Fluorescence in situ hybridisation with clone RP11-261A7 showed an amplified signal in the larger chromosome 16. This clone contains FLJ43855 gene, similar to sodium- and chloride-dependent creatine transporter. So, this 16p+ variant that involves amplification of pseudogenetic sequences is considered a polymorphism in normal individuals.

Masking of the clinical severity of severe haemophilia A in a patient with β‐thalassemia major—its implications in prenatal diagnosis

Masking of the clinical severity of severe haemophilia A in a patient with β‐thalassemia major—its implications in prenatal diagnosis