Canadian College of Medical Geneticists: clinical practice advisory document - responsibility to recontact for reinterpretation of clinical genetic testing.

BACKGROUND: Advances in technology and knowledge have facilitated both an increase in the number of patient variants reported and variants reclassified. While there is currently no duty to recontact for reclassified genetic variants, there may be a responsibility. The purpose of this clinical practice advisory document is to provide healthcare practitioners guidance for recontact of previously identified and classified variants, suggest methods for recontact, and principles to consider, taking account patient safety, feasibility, ethical considerations, health service capacity and resource constraints. The target audience are practitioners who order genetic testing, follow patients who have undergone genetic testing and those analysing and reporting genetic testing. METHODS: A multidisciplinary group of laboratory and ordering clinicians, patient representatives, ethics and legal researchers and a genetic counsellor from the Canadian Association of Genetic Counsellors reviewed the existing literature and guidelines on responsibility to recontact in a clinical context to make recommendations. Comments were collected from the Canadian College of Medical Geneticists (CCMG) Education, Ethics, and Public Policy, Clinical Practice and Laboratory Practice committees, and the membership at large. RESULTS: Following incorporation of feedback, and external review by the Canadian Association of Genetic Counsellors and patient groups, the document was approved by the CCMG Board of Directors. The CCMG is the Canadian organisation responsible for certifying laboratory and medical geneticists who provide medical genetics services, and for establishing professional and ethical standards for clinical genetics services in Canada. CONCLUSION: The document describes the ethical and practical factors and suggests a shared responsibility between patients, ordering clinician and laboratory practitioners.

Prenatal findings in 11 cases with craniofacial microsomia using the Alberta Congenital Anomalies Surveillance System, 1997-2019.

Craniofacial microsomia (CFM) primarily includes specific head and neck anomalies that co-occur more frequently than expected. The anomalies are usually asymmetric and affect craniofacial features; however, there are frequently additional anomalies of variable severity. Published prenatal findings for CFM are limited. This study contributes 11 cases with CFM and their anomalies identified prenatally. Cases born between January 1, 1997 and December 31, 2019 with CFM were abstracted from the Alberta Congenital Anomalies Surveillance System, which is a population-based program ascertaining congenital anomalies for livebirths, stillbirths, and termination of pregnancies for fetal anomalies. There were 11 cases ascertained with prenatal findings including facial anomalies: one each with left cleft lip, right microtia, and bilateral microphthalmia. Two cases had vertebral anomalies. In addition, anomalies of the kidneys, brain, heart, and radial ray were identified. Six (55%) had a single umbilical artery, five (45%) were small for gestational age, and three (27%) were from a twin pregnancy that were discordant for anomalies. Four (36%) overlapped another proposed recurrent constellations of embryonic malformation condition. This study describes prenatal findings for 11 cases with CFM. Comparable to prior published cases, there were recurring anomalies on prenatal imaging, including anomalies of the brain, eye, heart, kidneys, and radial ray, which may aid in the prenatal diagnosis of CFM.

Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.

The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

Maternal Cytomegalovirus (CMV) Serology: The Diagnostic Limitations of CMV IgM and IgG Avidity in Detecting Congenital CMV Infection.

INTRODUCTION: Congenital cytomegalovirus (cCMV) is a common congenital viral infection. Testing for cCMV usually begins with assessing maternal CMV serology, specifically IgM and IgG antibodies. A negative maternal CMV IgM suggests a low risk of recent maternal CMV infection, thereby suggesting a low risk of cCMV in the fetus. Consequently, cCMV is often ruled out when maternal CMV IgM is negative. METHODS: In our perinatal autopsy and placental pathology database, we identified 5 cases of cCMV despite negative maternal CMV IgM results in the second trimester. RESULTS: In all 5 cases, fetal abnormalities were first detected by ultrasound in the second trimester, prompting maternal CMV testing. Since second trimester maternal CMV IgM was negative in all cases, cCMV was considered unlikely, thus precluding further prenatal CMV testing in 4 of these cases. The diagnosis of cCMV was subsequently made through placental and/or autopsy examinations. Following this diagnosis, retrospective CMV serology and IgG avidity testing was performed on stored frozen first-trimester maternal blood samples in 3 cases. Among these, the first-trimester samples in 2 cases were IgG+, IgM+, and exhibited low IgG avidity, suggesting a primary maternal CMV infection around the time of conception. In the third case, both first and second-trimester maternal blood samples were IgG+, IgM-, and showed high IgG avidity, suggesting a non-primary maternal CMV infection (i.e., reactivation or reinfection of CMV). CONCLUSION: A negative maternal CMV IgM in the second trimester cannot exclude cCMV infection. While CMV IgG avidity testing and analysis of stored frozen first-trimester maternal blood samples provide valuable insights, they have limitations. CMV PCR performed on amniotic fluid is a useful prenatal diagnostic tool. For cases of unexplained fetal abnormalities or death, autopsy and placental examination are recommended.

Lethal multiple pterygium syndrome, large cystic hygroma, and cleft palate: Rare and severe fetal presentations of RYR1- and NEB-related congenital myopathies.

Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present broadly. The most severe presentation is neonatal with arthrogryposis and, rarely, fetal akinesia and pterygia, features also seen in lethal multiple pterygium syndrome (LMPS). We describe two fetuses with similar phenotype, including hydrops fetalis, large cystic hygromas, bilateral talipes, and fetal akinesia in the second trimester. Genetic diagnoses were made using exome sequencing. Both fetuses had a severe form of congenital myopathy. In the first fetus, we identified two novel compound heterozygous likely pathogenic variants consistent with autosomal recessive RYR1-related congenital myopathy (congenital myopathy 1B). In the second fetus, we identified two likely pathogenic variants, one of which is novel, likely in trans consistent with a diagnosis of autosomal recessive NEB-related congenital myopathy. Reaching a genetic diagnosis for these fetuses allowed the families to receive accurate genetic counseling for future pregnancies. These fetuses highlight the genetic and phenotypic heterogeneity of LMPS, and support a broad approach to genetic testing.

Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.

Craniofacial Microsomia, Associated Congenital Anomalies, and Risk Factors in 63 Cases from the Alberta Congenital Anomalies Surveillance System.

OBJECTIVE: To report associated congenital anomalies with unexplained craniofacial microsomia (CFM) and the phenotypic overlap with other recurrent constellations of embryonic malformations (RCEM), and to assess prenatal and perinatal risk factors. STUDY DESIGN: This is a retrospective cross-sectional study. Cases with CFM, delivered between January 1, 1997, and December 31, 2019, were abstracted from the population-based Alberta Congenital Anomalies Surveillance System. Livebirths, stillbirths, and early fetal losses were reviewed to include all types of pregnancy outcomes along the spectrum of this condition. Prenatal and perinatal risk factors were compared with the Alberta birth population to assess differences between the 2 groups. RESULTS: There were 63 cases with CFM, yielding a frequency of 1 per 16 949. There was a high rate of cases (65%) with anomalies outside the craniofacial and vertebral regions. Congenital heart defects were the most common (33.3%). A single umbilical artery was found in 12.7% of cases. The twin/triplet rate of 12.7% was significantly higher than the Alberta rate of 3.3% (P < .0001). There was an overlap with a second RCEM condition in 9.5% of cases. CONCLUSIONS: Although CFM is primarily a craniofacial condition, the majority of cases have congenital anomalies affecting other systems requiring additional assessments, including an echocardiogram, renal ultrasound examination, and a complete vertebral radiograph. The high rate of an associated single umbilical artery raises the possibility of a related etiological mechanism. Our findings support the proposed concept of RCEM conditions.

Prenatal Diagnosis of Isolated Right Ventricular Non-Compaction Cardiomyopathy with an MYH7 Likely Pathogenic Variant.

Background: Noncompaction of ventricular myocardium is a cardiomyopathy that typically involves the left ventricle or both ventricles; it has often been associated with mutations in genes encoding sarcomere proteins. Little is known about isolated right ventricular noncompaction, as only a few cases have been reported. Case Report: A 30 year old G2P1 woman experienced a spontaneous fetal loss at 19 weeks and 4 days. An ultrasound examination at 19 weeks showed right ventricular and tricuspid valve abnormalities, ascites, and early hydrops. At autopsy, the right ventricular chamber was dilated with numerous prominent trabeculations and deep intrabecular recesses as well as a dysplastic tricuspid valve. Histologic examination confirmed isolated right ventricular noncompaction. Whole exome sequencing showed a likely pathogenic variant in the MYH7 gene. Conclusions: This appears to be the first report of isolated right ventricular noncompaction associated with a gene mutation as well as the first diagnosis in a fetus.

Growth, development, and phenotypic spectrum of individuals with deletions of 2q33.1 involving SATB2.

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.

Diffuse Intracerebral Hemorrhage in an Infant With a Novel Homozygous Variant Leading to Severe Protein C Deficiency.

Protein C is a circulating anticoagulant that inhibits factor Va and VIIIa and promotes fibrinolysis. Compound heterozygous or homozygous variants in the Protein C gene (PROC) lead to severe deficiency of protein C and affected neonates typically present shortly after birth with purpura fulminans. We describe an infant who suffered a diffuse intracranial hemorrhage as a neonate and presented with purpura fulminans as an older infant which led to investigations that were consistent with severe protein C deficiency. We demonstrate subacute findings on neuroimaging and suggest this condition should be considered with neonatal presentations of bilateral intraparenchymal hemorrhage.

Re-evaluating the first-tier status of fragile X testing in neurodevelopmental disorders.

PURPOSE: Evaluate whether fragile X syndrome (FXS) testing should be transitioned to a second-tier test in global developmental delay, intellectual disability, and autism spectrum disorder in the absence of family history and suggestive clinical features. METHODS: Determine the diagnostic yield of FXS testing performed by the Alberta Children's Hospital (ACH) Molecular Diagnostic Laboratory between 2012 and 2017. Retrospective chart review of FXS-positive patients to determine presence or absence of suggestive clinical features and family history. RESULTS: Of the 2486 pediatric patients with neurodevelopmental disorders tested for FXS, 25 males and 5 females were positive. This corresponds to a 1.2% diagnostic yield of FXS testing at our center. Retrospective chart review of the FXS-positive cases revealed that 96% of FXS patients had either, if not both, clinical features or family history suggestive of FXS present at the time of testing. Only one patient had neither family history nor clinical features suggestive of FXS. CONCLUSION: In 96% of FXS-positive cases, there was sufficient clinical suspicion raised on the basis of clinical features and/or family history to perform targeted FXS testing. We thus propose that in the absence of suggestive clinical features or family history, FXS testing should be transitioned to a second-tier test in neurodevelopmental disorders.

Prevalence rates study of selected isolated non-Mendelian congenital anomalies in the Hutterite population of Alberta, 1980-2016.

A study of the prevalence rates for selected isolated non-Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs-Raine et al., 2016). Cases were ascertained from the Alberta Congenital Anomaly Surveillance System for the years 1997-2016. Since our initial results showed some surprising findings in the Hutterite Brethren, such as zero cases of spina bifida, cleft lip and palate, gastroschisis, and omphalocele, and a significant excess of cases with hypospadias, we extended the study to prior years (1980-1996) for selected anomalies. For the extended study period (1980-2016), there was a significant increased prevalence of hypospadias, tetralogy of Fallot and tricuspid atresia in the Hutterite population, and although not statistically significant, zero cases of cleft lip with cleft palate, gastroschisis and omphalocele were confirmed. Further research is needed to determine the precise effects of rural environmental exposures, lifestyle factors, and genetic associations for selected multifactorial congenital anomalies.

Congenital hiatal hernia segregating with a duplication in 9q22.31q22.32 in two families.

Congenital hiatal hernia (HH) is a rare congenital defect and is often described on a sporadic basis, but familial cases have also been reported. The mechanism of development is not well understood, and to our knowledge no specific genetic factors have been implicated to date. We report on seven individuals from two families with 9q22 duplication, who have variably associated features including congenital HH in four individuals. One family had an 1.09 Mb 9q22 duplication, and the other family had an overlapping 2.73 Mb 9q22 duplication. We review the genes in this region and discuss BARX1 (BarH-like homeobox gene 1) as a gene of interest.

Correction: A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.

BACKGROUND: The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. METHODS: A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. RESULTS AND CONCLUSIONS: Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9).

A Challenging Prenatal QF-PCR Rapid Aneuploidy Test Result Caused by a Maternally Inherited Triplication within Chromosome Xq26.2.

The aim of this study was to investigate the origin of the biallelic trisomic amplification pattern of the X chromosome microsatellite marker DXS1187 in an otherwise normal male fetus, identified on routine rapid aneuploidy detection (RAD) testing by quantitative fluorescent-polymerase chain reaction (QF-PCR). Amniocentesis was performed on a 35-year-old female at 15 weeks, 2 days gestation for a positive first trimester screen. QF-PCR, metaphase FISH, and chromosomal microarray were carried out on both maternal and fetal DNA. Fetal QF-PCR showed a biallelic trisomic pattern for the X chromosome microsatellite marker DXS1187, with an otherwise normal male amplification pattern at all other sex chromosome markers. Chromosome analysis performed on cultured amniocytes showed a normal male karyotype. Chromosome microarray analysis identified a maternally inherited 304-kb copy number triplication within chromosome Xq26.2 encompassing the DXS1187 marker. The maternally inherited X chromosome harbors an apparently tandem 304-kb triplication that overlaps the DXS1187 marker. As the triplicated region is devoid of clinically relevant genes, it was considered as likely benign in the fetus. Postnatal follow-up reported a healthy male newborn. To our knowledge, this is a unique case demonstrating a "benign" copy number imbalance involving the DXS1187 marker detected by prenatal QF-PCR RAD.

Next-Generation Sequencing Using a Cardiac Gene Panel in Prenatally Diagnosed Cardiac Anomalies.

OBJECTIVE: Most prenatally identified congenital heart defects (CHDs) are the sole structural anomaly detected; however, there is a subgroup of cases where the specific genetic cause will impact prognosis, including chromosome abnormalities and single-gene causes. Next-generation sequencing of all the protein coding regions in the genome or targeted to genes involved in cardiac development is currently possible in the prenatal period, but there are minimal data on the clinical utility of such an approach. This study assessed the outcome of a CHD gene panel that included single-gene causes of syndromic and non-syndromic CHDs. METHOD: Sixteen cases with a fetal CHD identified on prenatal ultrasound were studied using a 108 CHD gene panel. DNA was extracted from cultured amniocytes. RESULTS: There was no diagnostic pathogenic variant identified in these cases. There was an average of 2.9 reportable variants identified per case and the majority of them were variants of uncertain significance. CONCLUSION: Next-generation sequencing has the potential for increased genetic diagnosis for fetal anomalies. However, the large number of variants and the absence of an examinable patient make the interpretation of these variants challenging.

Mosaic trisomy 1q: a recurring chromosome anomaly that is a diagnostic challenge and is associated with a Fryns-like phenotype.

OBJECTIVE: Trisomy of the long arm of chromosome 1 is a very rare cytogenetic anomaly that is difficult to diagnose because of tissue-limited mosaicism. This study aimed to further characterize the prenatal and post-natal findings associated with this anomaly, including the first reported chromosomal microarray finding. METHOD: This is a retrospective study of six cases of mos 46,X,der(Y)t(Y;1)(q12;q21)/46,XY, diagnosed both prenatally and post-natally. Detailed clinical features and pregnancy outcome were documented. RESULTS: Recurrent prenatal and post-natal features of our case series, as well as the previously reported cases, were described, suggesting a Fryns-like phenotype. A diagnosis of mosaic trisomy 1q is difficult to confirm post-natally in some cases because of the tissue provided for analysis, emphasizing the need to study multiple tissue types in cases of fetal loss with a suspected underlying chromosomal imbalance. CONCLUSION: The overlap of clinical features between mosaic trisomy 1q and Fryns syndrome emphasizes the need to obtain appropriate samples for genetic analysis. The present cases and a review of the literature suggest that partial trisomy of the long arm of chromosome 1 is a distinct de novo clinical entity with low recurrence risk. © 2017 John Wiley & Sons, Ltd.