We reportthefirst caseofaninterstitial deletion ofthedistal longarm ofchromosome 4 (q31.22-+q34.2). The major clinical features aredescribed andcomparedtothoseofotherpublished reports ofdel4q,mainlythosesharing acommon deleted segmentwiththepresentcase (bothinterstitial and terminal). This comparison suggests thatthecharacteristicphenotypeattributed toterminal deletions of4q31-*qter probably mainly resultsfrom lossof the segment q31-*q33-34.

Interstitial deletion ofthedistal long arm of chromosome 4

To investigate the incidence and clinical significance of chromosomal mosaicism (CM) in prenatal diagnosis by G-banding karyotyping and chromosomal microarray analysis (CMA). This is a single-centre retrospective study of invasive prenatal diagnosis for CM. From 5758 karyotyping results and 6066 CMA results, 104 foetal cases with CM were selected and analysed further. In total, 50% (52/104) of foetal cases with CM were affected by ultrasound-detectable phenotypes. Regardless of whether they were singleton or twin pregnancies, isolated structural defects in one system (51.35%, 19/37 in singletons; 86.67%, 13/15 in twins) and a single soft marker (18.92%, 7/37 in singletons; 13.33%, 2/15 in twins) were the most common ultrasound anomalies. Mosaic autosomal trisomy (19.23%, 20/104) was the most frequent type, and its rate was higher in phenotypic foetuses (28.85%, 15/52) than in non-phenotypic foetuses (9.62%, 5/52). There was no difference in mosaic fractions between phenotypic and non-phenotypic foetuses based on specimen sources or overall classification. Discordant mosaic results were observed in 16 cases (15.38%, 16/104) from different specimens or different testing methods. Genetic counselling and clinical management regarding CM in prenatal diagnosis remain challenging due to the variable phenotypes and unclear significance. Greater caution should be used in prenatal counselling, and more comprehensive assays involving serial ultrasound examinations, different specimens or testing methods verifications and follow-up should be applied.

Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis.

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions (90%), encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), or by pathogenic variants in RAI1 itself (10%). RAI1 is a dosage-sensitive gene expressed in many tissues and acting as transcriptional regulator. The majority of individuals exhibit a mild-to-moderate range of intellectual disability. The behavioral phenotype includes significant sleep disturbance, stereotypes, maladaptive and self-injurious behaviors. In this review, we summarize current clinical knowledge and therapeutic approaches. We further discuss the common biological background shared with other conditions commonly retained in differential diagnosis.

/pdf/smith-magenis-syndrome-clinical-review-biological-background-3hj654vi.pdf

Smith-Magenis Syndrome—Clinical Review, Biological Background and Related Disorders

Following an ultrasound examination indicating an elevated risk of a fetal chromosomal abnormality, pregnant women are offered prenatal genetic testing to more accurately identify the anomalies' etiology and fetal prognosis. Follow-up genetic testing usually includes G-band karyotyping and/or chromosomal microarray analysis (CMA). These techniques involve an invasive diagnostic procedure such as chorionic villus sampling or amniocentesis, although such procedures are not acceptable for a considerable number of pregnant women because of the procedure-related risk of miscarriage. Noninvasive prenatal testing (NIPT) of cell-free DNA (cfDNA) frommaternal plasma is a potential alternative; this requires only a maternal blood sample to perform. Trisomies 13, 18, and 21 have been detected by NIPT with a high degree of sensitivity and specificity. Detection of subchromosomal copy-number variants using NIPT is also plausible. The aims of this retrospective study were to evaluate the efficacy of NIPT as an alternative to invasive prenatal testing for the detection of fetal genetic aberrations following abnormal ultrasound findings. The study included pregnancies found to be at risk of fetal chromosomal abnormality based on sonographic testing, in which NIPTwas used as a follow-up genetic test. Medical records were reviewed for relevant data including maternal age, initial sonographic findings, results of NIPT, results of any diagnostic genetic testing, and pregnancy outcome. Health, Inc. All rights reserved.

/pdf/clinical-utility-of-noninvasive-prenatal-testing-in-jl8u133a21.pdf

Clinical Utility of Noninvasive Prenatal Testing in Pregnancies With Ultrasound Anomalies

Several studies have reported on the maternal age‐associated risks of congenital anomalies. However, there is a paucity of studies with comprehensive review of anomalies. We aimed to quantify the risk of birth defects in children born to middle‐aged mothers compared with that in children born to young or older mothers.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/aogs.14339

Congenital anomalies and maternal age: A systematic review and meta‐analysis of observational studies

Cordocentesis in our practice is most commonly indicated for rapid karyotyping in the second or third trimester and is regarded as the gold standard for foetal chromosomal aberration diagnosis in pregnancies at high risk for chromosomal abnormalities. In this study, we investigated 3387 umbilical cord blood samples for karyotyping from pregnant women who underwent cordocentesis and explored the pregnancy outcomes of foetal sex chromosome mosaicism and chromosomal polymorphism. Out of the 3387 samples, 182 abnormal karyotypes were detected. Ultrasound soft markers were the most common prenatal diagnostic indication, but the detection rate of abnormal karyotypes was 2.02%, while it was 46.97% in the genome-wide NIPT-positive group. The rate of aneuploidy was lower in the soft marker group than in the other groups. Out of 16 cases with sex chromosome mosaicism, three pregnant women with foetuses with a lower proportion of sex chromosome mosaicism delivered healthy foetuses; the foetus with karyotype 46,X,i(Y)(q10)[20]/45,X[6] showed unclear genitals. Three foetuses with chromosomal polymorphisms had postnatal disorders. NIPT should not be recommended as the first-tier screening for chromosomal aberration for pregnancies with ultrasound soft markers or pathological ultrasound findings, but NIPT can be considered an acceptable alternative for pregnancies with contraindications to cordocentesis or the fear of procedure-related foetal loss. Mosaicism found in amniotic fluid cell culture requires further cordocentesis for karyotype confirmation, and the continuation of pregnancy is safe when a normal karyotype is identified in foetal blood culture. Further genetic testing and parental karyotype analysis are needed for foetal chromosomal polymorphisms.

/pdf/cytogenetic-analysis-of-3387-umbilical-cord-blood-in-3vvzqs8rax.pdf

Cytogenetic analysis of 3387 umbilical cord blood in pregnant women at high risk for chromosomal abnormalities.

As an important factor of chromosome abnormality in offspring, elderly pregnant women have attracted more and more attention. Studies have confirmed that the offspring of older pregnant women, whether conceived naturally or through assisted reproductive technology, are more likely to develop chromosome abnormalities than younger pregnant women, and the reasons have not been fully explained. The spindle assembly checkpoint monitors the correct connection between all mobile axes and the spindle. The bipolar spindle is the key to cell division to guide the correct separation of chromosomes and is the main gatekeeper to prevent the development of oocytes carrying DNA damage. Older pregnant women lead to the error of sister chromatid separation and the decrease of chromosome cohesion. The integrity of telomeres also affects the folding of DNA and the ability of cells to replicate. In addition, more oxidative stress makes the ovaries of older pregnant women unable to support fertilization and embryonic development. With the oxygen free radicals increase, the pathway of ovarian cell apoptosis and mitochondrial repair were changed. Therefore, the analysis of the causes of fetal chromosome abnormalities in elderly pregnant women is helpful to improve the understanding of the particularity of pregnancy in elderly pregnant women, so as to reduce the birth of defective babies and improve the birth quality.

/pdf/the-risk-of-advanced-maternal-age-causes-and-overview-4mtks34cln.pdf

The Risk of Advanced Maternal Age: Causes and Overview

Smith-Magenis syndrome (SMS, OMIM: 182290) is a multiple congenital anomalies and intellectual disability syndrome due to a 3.45 Mb microdeletion involving 17p11.2 and is estimated to occur about one in 25,000 births. Up to now, the ultrasound findings of the foetus with SMS and their external genital defects in patients are rarely reported. This case indicates that foetus with SMS may presentpolyhydramnios and ventriculomegaly in the second trimester. The newborn male patient had an abnormal phenotype in which he has micropenis and his anus is close to the perineal body. The identification of this case may further expand the phenotypic spectrum of this genetic disorder.

Prenatal diagnosis and neonatal phenotype of a de novo microdeletion of 17p11.2p12 associated with Smith-Magenis syndrome and external genital defects

Although Chromosomal microarray analysis (CMA) is a powerful diagnostic technology for detecting chromosomal copy number variants (CNVs), it detects numerous variants of unknown significance (VUSs), which poses a great challenge for genetic counselling. Terminal deletion of the long arm of chromosome 4 is a rare genetic aberration. Few cases of interstitial deletion sharing the common deleted segment have been reported. A male foetus with a 7.22-Mb deletion at chromosome 4q32.2q32.3 was found in the proband. The paternal genotype was normal. His asymptomatic mother with a normal phenotype and intelligence was found to carry the same deletion at the long arm of chromosome 4. The clinical significance of arr[GRCh37] 4q32.2q32.3(162858958_170081268)×1 remains uncertain. To the best of our knowledge, this is the first case report on a VUS of 4q32 deletion and the second report of a heterochromatic CNV involving part of the long arm of chromosome 4 in a phenotypically normal mother and child. The identification of this case contributes to additional understanding of deletion at 4q32.2q32.3. This report may provide a reference for prenatal diagnosis and genetic counselling in patients who have genotypes of similar cytogenetic abnormalities. The novel 7.22-Mb deletion at chromosome 4q32.2q32.3 (162858958-170081268) is a VUS. The foetus inherited this VUS from a phenotypically normal mother.

https://link.springer.com/content/pdf/10.1186/s13039-020-00480-8.pdf

Prenatal diagnosis of a maternal 7.22-Mb deletion at chromosome 4q32.2q32.3 by SNP array

Complex chromosomal rearrangements (CCR) are rare chromosomal structural abnormalities. The chromosomal structural variants in CCR carriers are one of the factors contributing to a history of adverse pregnancy and childbirth. In this study, we report a patient with a history of adverse pregnancy and childbirth who exhibited complex balanced chromosomal translocations. The female patient was phenotypically and intellectually normal; in her first pregnancy, the embryo was damaged, and a histological examination of the chromosomes of the embryos revealed a deletion of approximately 4.66 Mb at 1p32.3p32.2, a duplication of approximately 1.02 Mb at 1p22.2p22.1, a duplication of approximately 1.46 Mb at 6q27 and a deletion of approximately 7.78 Mb at 9p24.3p24.1. Chromosomal examinations of the patient revealed the karyotype to be 46,XX,(1;9)(p32; p34). In the second pregnancy, the foetus was diagnosed prenatally with three or more positive ultrasound soft indicators. The patient's karyotype was re-examined and further confirmed by fluorescence in situ hybridisation as 46,XX,t(1;9;6)(p31;p22;q27), revealing this patient was a carrier of complex balanced chromosomal translocations. Carriers of CCR have a higher risk of spontaneous abortion, and genetic counselling clinicians should consider the karyotype analyses of such patients in clinical practice and recheck their chromosomes if necessary. 

/pdf/a-case-of-complex-balanced-chromosomal-translocations-274v7l6q.pdf

Pingping Zhang

Papers

Cytogenetic analysis of 3387 umbilical cord blood in pregnant women at high risk for chromosomal abnormalities.

The Risk of Advanced Maternal Age: Causes and Overview

Prenatal diagnosis and neonatal phenotype of a de novo microdeletion of 17p11.2p12 associated with Smith-Magenis syndrome and external genital defects

Prenatal diagnosis of a maternal 7.22-Mb deletion at chromosome 4q32.2q32.3 by SNP array

A case of complex balanced chromosomal translocations associated with adverse pregnancy outcomes