Prenatal diagnosis by whole exome sequencing in a family with a novel TBR1 mutation causing intellectual disability

ObjectiveTo provide prenatal diagnosis for a pregnant woman with genetic history of intellectual disability.Case reportA Chinese pedigree with intellectual disability was collected in this study. Cytogenetic analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) followed by Sanger validation were conducted to identify the genetic pathogenesis. A novel heterozygous deletion c.370_374delTTCCC in TBR1 gene was identified, leading to a frameshift mutation starting at Phe124 followed by a premature stop codon at position 141 (p.Phe124Valfs118). Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. Prenatal diagnosis indicated the absence of this mutation, and the family decided to continue the pregnancy after genetic counseling.ConclusionOur findings demonstrated the significance of genetic testing in the diagnosis of intellectual disability. This work also confirmed the effectiveness of WES in prenatal diagnosis.     

Noonan syndrome: Prenatal diagnosis in a woman carrying a PTPN11 gene mutation

Objective.?To describe the case of a pregnant woman and her fetus with Noonan syndrome (NS) whom were diagnosed through ultrasonography 3D and molecular analysis of the PTPN11 gene.

Study design.?Case report.

Results.?We detected in a pregnant woman and her child the G<A transition at position 236 in exon 3 of the PTPN11 gene causative of NS. Antenatal diagnosis was possible through ultrasonography in the 24th week of gestation.

Conclusions.?Ultrasonography 3D is useful in the antenatal diagnosis of major congenital anomalies. Molecular studies should also be included to confirm the specific diagnosis.     

Whole exome sequencing identifies a novel FRAS1 mutation and aids in vitro fertilization with preimplantation genetic diagnosis in Fraser syndrome

ObjectiveTo demonstrate the picture of a woman who had three times of pregnancies but fetuses were complicated with Fraser syndrome, a rare genetic disorder with multiple congenital anomalies.Case reportHere are three complicated pregnancies with predominant features of severe oligohydramnios and other variable intrafamilial presentations. We made a definite diagnosis, Fraser syndrome, with the assistance of whole exome sequencing (WES) via umbilical blood of the second and third fetus. The provision of a preimplantation diagnosis helped contribute a healthy newborn in this family.ConclusionThis paper provides insights into obscure antenatal presentations of Fraser syndrome with intrafamilial variance. Clinical uncertainty at the fetal stage suggests the role of WES to reach a final diagnosis, and a preimplantation diagnosis is applicable to avoid recurrence of genetic disorders in subsequent pregnancies.     

Cystic adenomatoid malformation of the lung causing hydrops fetalis: case report and review of the literature

Objective  Fetal congenital cystic adenomatoid malformation (CCAM) is a rare lung abnormality with a highly variable prognosis depended on the presence of fetal hydrops and the size of the cysts. In case of fetal hydrops the prognosis is fatal without intervention. Methods and design  Case report and literature review. Setting  We report on the ultrasound and pathological findings of a hydropic fetus due to a CCAM Type II at 22 weeks of gestation. Conclusions  Congenital cystic adenomatoid malformation is a rare fetal lung disease with an excellent prognosis in the absence of fetal hydrops. CCAM associated with fetal hydrops carries a grave prognosis but survival rates of 70% can be achieved by thoraco-amniotic drainage in those with macrocystic lesions. S. Schott, G. Meyberg-Solomayer, and K. O. Kagan have contributed equally to the senior authorship.     

L1CAM mutations in three fetuses diagnosed by medical exome sequencing

ObjectiveThe L1 cell adhesion molecule (L1CAM) gene, encodes the L1 cell adhesion molecule, is involved in the central nervous system development. Its mutations result in L1 syndrome which is associated with brain malformation and nervous developmental delay.Case reportWe presented three fetuses with hydrocephalus and agenesis of the corpus callosum detected by ultrasound, followed by medical exome sequencing (MES) test with L1CAM mutations: two known missense mutation c.551G > A (p. R184Q) and c.1354G > A (p. G452R), and a novel frameshift mutation c.1322delG which causes the early termination of translation (p. G441Afs172). By utilizing multiple computational analysis, all the variants were scored to be likely pathogenic.ConclusionCombined use of ultrasound and MES to identify the molecular etiology of fetal anomalies may contribute to expanding our knowledge of the clinical phenotype of L1 syndrome observed in the south Chinese population.     

A novel nonsense mutation of TGFBR1 in a fetus with untypical Loeys-Dietz syndrome 1

ObjectiveWe present a rare untypical Loeys-Dietz syndrome 1 case in prenatal setting and report a novel mutation in the TGFBR1 gene.Case reportA pregnant woman came for medical attention due to the fetal ultrasound anomaly. The fetus was found to have short long bones. Trio-based WES was applied to the family. A novel de novo nonsense mutation c.1237C > T was detected in the TGFBR1 gene. A diagnosis of Loeys-Dietz syndrome 1 (LDS1) was plausible, but the fetus did not demonstrate the characteristic phenotype of the syndrome.ConclusionIn prenatal setting, fetal phenotypes are difficult to be fully observed, putting stress on the utility of molecular techniques. LDS1 in fetuses could present untypical features such as skeletal dysplasia.     

非免疫性胎儿水肿综合征的遗传学因素及妊娠结局分析

目的探讨非免疫性胎儿水肿综合征(nonimmune hydrops fetalis,NIHF)非重型α地中海贫血胎儿的遗传学原因及妊娠结局。 方法回顾性分析2014年1月至2020年7月在广州医科大学附属第三医院超声诊断为非免疫性胎儿水肿综合征病例116例,通过染色体核型分析/染色体微阵列分析(chromosome microarray analysis,CMA)/全外显子组测序(whole exome sequencing,WES)进行产前诊断,并分析其妊娠结局。 结果103例单胎NIHF中45例(43.69%,45/103)有临床显著的产前诊断结果异常,其中30例染色体数目异常,9例有致病性/可能致病性拷贝数变异,6例有致病性/可疑致病/临床意义未明的变异。13例双胎及多胎之一NIHF中5例为非整倍体。81例单胎选择人工终止妊娠。19例单胎继续妊娠,除8例胎死宫内外,11例活产(6例早产,5例足月产);其中4例(3例早产、1例足月产)接受了出生后手术(1例行室间隔修补术,1例行腹腔穿刺引流术,1例行回肠双腔造口术,1例行肠梗阻手术),3例成功,1例术后夭折;6例未行手术者除1例生长发育迟缓,余生长发育正常。 结论NIHF主要的遗传学病因是非整倍体异常、CNV异常及点突变,CMA对胎儿遗传学病因的检出率高于染色体核型分析,应被用于一线检查手段;WES是诊断NIHF的一个非常有价值的工具,可以发现罕见单基因遗传病。     

Prenatal diagnosis of familial recessive PIGN mutation associated with multiple anomalies: A case report

ObjectiveWe present a novel homozygous splice site mutation in the PIGN gene identified by whole exome sequencing and explored the genotype–phenotype correlation.Case reportA healthy 32-year-old woman underwent an ultrasound at 13 + 5 weeks of gestation. The ultrasound revealed multiple anomalies again including cystic hygroma, omphalocele and a ventricular septal defect. The pregnancy was subsequently terminated, and whole exome sequencing revealed a novel homozygous splice site mutation in the PIGN gene c.963 G > A (p.Gln321Gln). The same variant was also detected by pedigree-based Sanger sequencing in both parents as heterozygous, while they had normal karyotypes.ConclusionOur case report enhances the phenotype–genotype correlation associated with homozygous loss of function mutations in the PIGN gene.     

Prenatal diagnosis of scrotal-inguinal hernia: two case reports and review of the English literature

We present two cases of a prenatal diagnosis of inguinal hernia and the fetal outcome. Initial differential diagnosis included sacrococcygeal teratoma and testicular termatoma, while the final diagnosis was scrotal-inguinal hernia based on sonographic visualization of bowel loop movement in the scrotal mass.     

单纯性染色体18p部分三体综合征患儿的产前遗传学诊断和文献回顾

目的探讨单纯性染色体18P部分三体综合征患者的产前诊断特点。方法联合运用传统染色体核型分析和染色体微阵列(chromosome microarray analysis,CMA)基因芯片技术对家系成员行染色体核型分析和基因组拷贝数变异检测。结果胎儿羊水染色体核型结果为46,XY,der(18),父母双方染色体核型均未见异常;胎儿基因芯片检测结果为arr[hg19]18p11.31p11.21(3,521,718-15,099,116)×3,即胎儿基因组18号染色体短臂p11.31p11.21区域存在11.58 Mb的片段重复,父母双方基因芯片结果均为阴性,提示该胎儿的18号染色体结构重排为新发生的。结论在一个有不良生育史家系的胎儿中检出一个罕见新发的单纯性染色体18p部分三体变异,这是世界少见的单纯性染色体18p部分三体综合征的产前病例报道。联合运用传统染色体核型分析和C M A基因芯片技术在预防不良产史家系中胎儿出生缺陷的产前诊断中具有重要的临床应用价值。     

Neonatal Bartter syndrome and unilateral ectopic renal cyst as new renal causes of hydrops fetalis: two case reports and review of the literature

Abstract

Non-immune hydrops fetalis (NIHF) is a challenging entity as it represents the end stage of several different disorders. Renal and genitourinary causes of NIHF are rare and include congenital renal malformations, tumors and ureter-urethra disorders. Herein, two NIHF cases with different renal causes were presented. The first case that had antenatal NIHF was diagnosed neonatal Bartter syndrome. The second case of NIHF with antenatal large cyst in the surrenal gland area required surgery and ectopic renal cyst was diagnosed. To our best of knowledge, these are the first reports of NIHF associated with neonatal Bartter syndrome and ectopic renal cyst in neonates. Although it may be coincidental, these cases suggest that both neonatal Bartter syndrome and unilateral ectopic renal cyst may cause NIHF development in neonates by several different mechanisms. Therefore, these two rare entities should be suspected in cases of NIHF with similar findings.     

Prenatal diagnosis of prune-belly syndrome at 13 weeks of gestation: case report and review of literature

We present a case report of a foetus with Prune-Belly syndrome (PBS) which was diagnosed sonographically during the 13th week of gestation and review of the literature. Sonographic diagnosis was based on abnormally distended urinary bladder and abdomen and absence of ‘keyhole sign’. Termination was performed on parental request and post-mortem examination revealed absence of abdominal wall musculature and the distended urinary bladder in a male foetus. Prenatal diagnosis of PBS is based on ultrasound and is usually diagnosed in the second trimester. In the first trimester there are very few reports to date. Prognosis and possible treatment options are herein discussed as well as the underlying mechanisms that may explain the clinical presentation of the syndrome.     

Prenatal diagnosis of de novo isochromosome 4p with an unbalanced t(4;9) translocation in a fetus with congenital anomalies: A case report and literature review

ObjectiveWe present the first case of prenatally diagnosed isochromosome 4p with whole 4q arm translocating to chromosome 9p23 and review the literature.Case ReportA 26-year-old woman underwent amniocentesis at 25 weeks of gestation because of an abnormal ultrasound examination. Routine chromosome analysis on cultured amniocytes showed a karyotype of 46,XX, ?idic(4)(q11),der(9)t(4;9)(q11;p23). Single nucleotide polymorphism (SNP) array analysis on uncultured amniocytes detected two copy number variations (CNVs): arr [GRCh37] 4p16.3p11(68345-49089361) × 3; arr [GRCh37] 9p24.3p23(208454-10039391) × 1. The karyotypes of the parents were normal, indicating that the chromosomal rearrangement was de novo. According to the fetal-parent trios SNP analysis, both the abnormal chromosomes were originated from the father. The pregnancy was terminated at 30 weeks of gestation, and a malformed fetus was delivered with dysmorphic craniofacial, short neck, wide-spaced nipples and rocker-bottom feet.ConclusionThe combined application of traditional cytogenetic technology and molecular diagnosis technology in prenatal diagnosis helps identify genetic components and the origin of isochromosome, which enable clinicians to precisely predict the fetal prognosis and provide accurate genetic counselling and fertility guidance.     

Prenatal diagnosis of congenital nephrotic syndrome of the Finnish type in a Chinese family

ObjectiveTo explore the genetic bias in a Chinese family suspected of having congenital nephrotic syndrome of the Finnish type (CNF).Case reportWe developed a prenatal genetic diagnosis in a Chinese family with CNF. A single heterozygous mutation (c.3213delG) was found in the foetus IId and we presumed that it was an asymptomatic carrier of the normal phenotype. Additionally, two compound heterozygous variants (c.3213delG and c.3478C > T) were discovered in the foetus IIe, which were inherited from the mother and father, respectively. We performed further pathological examinations after medical abortion. Kidney histopathology and immunofluorescence results were similar to those reported in previous studies.ConclusionPrenatal genetic diagnosis of CNF still requires further research to explore the pathogenicity of suspected mutations.     

Prenatal Marfan syndrome: report of one case and review of the literature

OBJECTIVES: Our objective was to describe the features of prenatal Marfan syndrome. METHODS: Doppler fetal echocardiograms were performed. The morphology and rhythm of the fetal heart were examined sequentially. RESULTS: The case was referred because of cardiomegaly and dilated great vessels. Sequential Doppler echocardiographic evaluation led to the diagnosis of prenatal Marfan syndrome. The main features are cardiomegaly, dysplastic atrioventricular valves with tricuspid regurgitation and dilated great vessels, which can be aneurysmal at their origin. The fetus died in utero at 39 weeks of gestation because of cardiac failure. Pathological study confirmed the Marfan habitus and complications. Molecular genetic study showed a de novo point mutation in exon 26 of the FBN1 gene. CONCLUSION: We report a case of prenatal Marfan syndrome diagnosed by sequential evaluation of the cardiac signs, which are essential for prenatal diagnosis. The prognosis seems as poor as the neonatal one. The prenatal diagnosis is essential for adequate counselling.     

Elevated CA125 level associated with Meigs' syndrome: case report and review of the literature

Abstract.   Morán-Mendoza A, Luna GA, Ruiz GC, Olvera AS, López Graniel CM, Rincón DG. Elevated CA125 level associated with Meigs' syndrome: case report and review of the literature. Int J Gynecol Cancer 2006; 16(Suppl. 1): 315–318.
Meigs' syndrome is the association of ovarian fibroma, pleural effusion, and ascites. Meigs' syndrome with marked elevation of CA125 is an unusual clinical condition reported in 27 cases in the literature. The patient was a 46-year-old woman with right pleural effusion, ascites, ovarian tumor, and CA125 level of 1808 U/mL. Tomography revealed ascites and bilobate pelvic tumor of approximately 25 cm. The diagnosis of advanced epithelial ovarian cancer was considered, and the patient was treated with chemotherapy. Three chemotherapy schemes were applied due to the total lack of response in tumor volume; however, CA125 decreased to 90 U/mL. Thus, surgery was performed with resection of 25 cm of the left ovarian tumor, with intact capsule and without implants; the result of histopathologic analysis was fibroma. Postoperative CA125 was 11 U/mL. Patients with elevated CA125 and ascites cytology positive for malignancy must be cautiously treated due to the possibility of false positives, even if the probability is low. Therefore, minimally invasive surgery for biopsy collection must be considered. Although the association between ovarian tumor, pleural effusion, ascites, and marked elevation of CA125 is highly indicative of epithelial ovarian cancer, Meigs' syndrome must be considered in the differential diagnosis.     

Molecular genetic characterization of a prenatally detected de novo interstitial deletion of chromosome 20p (20p12-p13) encompassing JAG1 and a literature review of prenatal diagnosis of Alagille syndrome

Objective

We present prenatal diagnosis and molecular genetic characterization of a de novo interstitial deletion of chromosome 20p (20p12-p13) and a literature review of prenatal diagnosis of Alagille syndrome (ALGS).

Prenatal screening characteristics in Emanuel syndrome: a case series and review of the literature

Purpose

Emanuel syndrome is a rare chromosomal disorder characterized by severe mental retardation and multiple anomalies. The syndrome is caused by chromosomal imbalance due to a supernumerary derivative chromosome 22. Little is known regarding the characteristics of prenatal biochemical screening, or ultrasonographic markers in this syndrome. We aimed to identify a prenatal screening pattern characteristic of Emanuel Syndrome.

Methods

We report the prenatal characteristics of five fetuses with Emanuel syndrome, four of which were diagnosed prenatally.

Results

We found no consistent pattern of prenatal biochemical markers or other prenatal characteristics. Nevertheless, increased NT, low PAPP-A and ultrasound features such as intra uterine growth restriction, posterior fossa, cardiac and bowel abnormalities may be helpful in raising the suspicion for this rare genetic syndrome.

Conclusion

Review of the biochemical screening results, ultrasound findings, and demographic characteristics of this Emanuel syndrome case series, as well as of the relevant literature fail to suggest a characteristic prenatal pattern.