Genetic analysis of a case with mosaicism complex structural aberration of chromosome 18 / 中华医学遗传学杂志

OBJECTIVE@#To determine the karyotype of a patient with mosaicism complex structural aberration of chromosome 18.@*METHODS@#A male patient with a 2-year history of infertility presented at the Center of Reproductive Medicine of the Third Hospital of Peking University in October 2019 was selected as the study subject. Clinical data of the patient was collected. Peripheral blood sample was taken for chromosomal karyotyping, copy number variation (CNV) analysis and fluorescence in situ hybridization (FISH) assay. Semen sample was taken for single sperm CNV analysis.@*RESULTS@#The patient was found to have a karyotype of mos 47,XY,del(18)(q21q23),+r(18)(q21q23)[84]/46,XY,del(18)(q21q23)[9]/48,XY,del(18)(q21q23),+r(18)(q21q23)×2[6]/47,XY,del(18)(q21q23),+r(18)(q21q23×2)[1].ish 47,XY,del(18)(q21q23),+r(18)(q21q23)[84]/46,XY,del(18)(q21q23)[9]/48,XY,del(18)(q21q23),+r(18)(q21q23)×2[6]/47,XY,del(18)(q21q23),+r(18)(q21q23×2)[1]del(18)(q21q23)(D18Z1+,18p+,18q+,WCP18+),r(18)(q21q23)(WCP18+),r(18)(q21q23×2)(WCP18+). No pathogenic CNV was identified. Sequencing of 20 single sperms showed that 1 sperm was normal, 1 had yielded no result, 9 had harbored del(18q), 7 had harbored dup(18q)×2, and 2 had harbored dup(18q)×3. The dup/del fragments had both spanned approximately 33 Mb.@*CONCLUSION@#It is rare for carriers of complex structural and numerical abnormalities of chromosome 18 to have a normal phenotype. Based on the accurate cytogenetic and molecular analyses and the single sperm CNV analysis, the influence of the aberrant karyotype on the gametogenesis may be evaluated.

Genetic features of a case with mosaic ring chromosome 4 and a review of the literature / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis, clinical phenotype and pathogenesis for a child with mosaicism ring chromosome 4.@*METHODS@#Clinical data of the child was collected. Peripheral blood chromosomal karyotype G banding analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH) were carried out for the child, in addition with a review of the literature.@*RESULTS@#The child was born full-term with low birth weight, facial dysmorphism, patent ductus arteriosus and ventricular septal defect. His karyotype was determined as mos46,XY,r(4)(p16.3q35.2)[259]/45,XY,-4[25]/47,XY,r(4)(p16.3q35.2), +r(4)(p16.3q35.2)[8]/46,XY,der(4)del(4)(p16.3)inv(4)(p16.3q31.1)[6]/46,XY,dic?r(4;4)(p16.3q35.2;p16.3q35.2)[4]/48,XY,r(4)(p16.3q35.2),+r(4)(p16.3q35.2)×2[3]/46,XY,r(4)(p1?q2?)[2]; CMA result was arr[GRCH37]4p16.3(68 345-2 981 614)×1; FISH result was 45,XY,-4[12]/45,XY,-4×2,+mar1.ish r1(4)(WHS-,D4Z1+)[1]/ 46,XY,-4,+mar1.ishr1(4)(WHS-,D4Z1+)[73]/46,XY,-4,+mar2.ishr2(4)(WHS-,D4Z1++)[1]/47,XY,-4,+mar1×2.ishr1(4) (WHS-, D4Z1+)×2[4]/46,XY,del(4)(p16.3).ish del(4)(p16.3)(WHS-,D4Z1+)[9].@*CONCLUSION@#In this case, the ring chromosome 4 as a de novo variant has produced a number of cell lines during embryonic development and given rise to mosaicism. The clinical phenotype of ring chromosome 4 is variable. The instability of the ring chromosome itself, presence of mosaicism, chromosome breakpoint and range of deletion and/or duplication may all affect the ultimate phenotype.

Mixed Gonadal Dysgenesis (45 X0/46 XV Mosaicism): A case report

@#Disorders of sexual development (DSD) defined as congenital conditions associated with atypical development of anatomical, gonadal or chromosomal sex, is a rare condition that may present with ambiguous genitalia. Included in the varied classes of DSD is mixed gonadal dysgenesis which is known to be due to mosaicism, a chromosomal aberration. Mosaic individuals may have concerns on growth, hormone balance, gonadal development, sex of rearing and fertility. This case report presents an 18-year old student who presented with primary amenorrhea, delayed secondary sexual characteristics and phenotypic features of Turner syndrome who, on chromosomal analysis revealed 45X0/46XY mosaicism. The patient underwent operative laparoscopy with bilateral gonadectomy on the basis of the increased risk of development of gonadal malignancy in phenotypic females with Y-chromosome material. Histopathological analysis revealed bilateral streak gonads. Hormone replacement therapy was then initiated for the induction of secondary female sex characteristics, as treatment for estrogen deficiency, for the induction of pubertal growth spurt and for optimization of bone mineral accumulation. Management of disorders of sexual development is challenging, thus the need for a multidisciplinary approach involving experts in endocrinology, gynecology, psychology and genetics.

Prenatal diagnosis and genetic analysis of a fetus with partial deletion of Yq and mosaicism of 45,X / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal diagnosis and genetic analysis for a fetus with disorders of sex development (DSDs).@*METHODS@#A fetus with DSDs who was identified at the Shenzhen People's Hospital in September 2021 was selected as the study subject. Combined molecular genetic techniques including quantitative fluorescence PCR (QF-PCR), multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray analysis (CMA), quantitative real-time PCR (qPCR), as well as cytogenetic techniques such as karyotyping analysis and fluorescence in situ hybridization (FISH) were applied. Ultrasonography was used to observe the phenotype of sex development.@*RESULTS@#Molecular genetic testing suggested that the fetus had mosaicism of Yq11.222qter deletion and X monosomy. Combined with the result of cytogenetic testing, its karyotype was determined as mos 45,X[34]/46,X,del(Y)(q11.222)[61]/47,X,del(Y)(q11.222),del(Y)(q11.222)[5]. Ultrasound examination suggested hypospadia, which was confirmed after elective abortion. Combined the results of genetic testing and phenotypic analysis, the fetus was ultimately diagnosed with DSDs.@*CONCLUSION@#This study has applied a variety of genetic techniques and ultrasonography to diagnose a fetus with DSDs with a complex karyotype.

Genetic analysis of a child with Pitt-Hopkins syndrome due to a novel variant of TCF4 gene derived from low percentage maternal mosaicism / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a child with Pitt-Hopkins syndrome.@*METHODS@#A child who had presented at the Medical Genetics Center of Gansu Provincial Maternal and Child Health Care Hospital on February 24, 2021 and his parents were selected as the study subjects. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. Karyotype analysis was also carried out for the child, and her mother was subjected to ultra-deep sequencing and prenatal diagnosis upon her subsequent pregnancy.@*RESULTS@#The clinical manifestations of the proband included facial dysmorphism, Simian crease, and mental retardation. Genetic testing revealed that he has carried a heterozygous c.1762C>T (p.Arg588Cys) variant of the TCF4 gene, for which both parents had a wild-type. The variant was unreported previously and was rated as likely pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (ACMG). Ultra-deep sequencing indicated that the variant has a proportion of 2.63% in the mother, suggesting the presence of low percentage mosaicism. Prenatal diagnosis of amniotic fluid sample suggested that the fetus did not carry the same variant.@*CONCLUSION@#The heterozygous c.1762C>T variant of the TCF4 gene probably underlay the disease in this child and has derived from the low percentage mosaicism in his mother.

Progress of research on chromosomal mosaicism embryos / 中华医学遗传学杂志

Chromosomal mosaicism (CM) is a common phenomenon in preimplantation genetic testing (PGT). In embryos with CM, genetic contents of trophoblastic ectodermal (TE) cells may be different from that of the inner cell mass (ICM) which will develop into the fetus. Embryos with low mosaic proportion could give rise to healthy live births after transplantation, but are accompanied with high pregnancy risks such as high abortion rate. In order to provide a more comprehensive understanding for CM embryos, this article has systematically summarized the recent progress of research on the definition, mechanism, classification, PGT techniques, self-correction mechanism, transplantation outcome and treatment principles for CM embryos.

The value of chromosomal microarray analysis and fluorescence in situ hybridization for the prenatal diagnosis of chromosomal mosaicisms / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) for the prenatal diagnosis of chromosomal mosaicisms.@*METHODS@#A total of 775 pregnant women who had visited the Prenatal Diagnosis Center of Yancheng Maternal and Child Health Care Hospital from January 2018 to December 2020 were selected as study subjects. Chromosome karyotyping analysis and CMA were carried out for all women, and FISH was used to validate the suspected mosaicism cases.@*RESULTS@#Among the 775 amniotic fluid samples, karyotyping has identified 13 mosaicism cases, which yielded a detection rate of 1.55%. Respectively, there were 4, 3, 4 and 2 cases for sex chromosome number mosaicisms, abnormal sex chromosome structure mosaicisms, abnormal autosomal number mosaicisms and abnormal autosomal structure mosaicisms. CMA has only detected only 6 of the 13 cases. Among 3 cases verified by FISH, 2 cases were consistent with the karyotyping and CMA results, and clearly showed low proportion mosaicism, and 1 case was consistent with the result of karyotyping but with a normal result by CMA. Eight pregnant women had chosen to terminate the pregnancy (5 with sex chromosome mosaicisms and 3 with autosomal mosaicisms).@*CONCLUSION@#For fetuses suspected for chromosomal mosaicisms, CMA, FISH and G-banding karyotyping should be combined to determine the type and proportion of mosaicisms more precisely in order to provide more information for genetic counseling.

Genetic analysis of a fetus with mosaic trisomy 12 and severe heart defects and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with severe heart defect and mosaic trisomy 12, and the correlation between chromosomal abnormalities and clinical manifestations and pregnancy outcome.@*METHODS@#A 33-year-old pregnant woman who presented at Lianyungang Maternal and Child Health Care Hospital on May 17, 2021 due to abnormal fetal heart development revealed by ultrasonography was selected as the study subject. Clinical data of the fetus were collected. Amniotic fluid sample of the pregnant women was collected and subjected to G-banded chromosomal karyotyping and chromosomal microarray analysis (CMA). The CNKI, WanFang and PubMed databases were searched with key words, with the retrieval period set as from June 1, 1992 to June 1, 2022.@*RESULTS@#For the 33-year-old pregnant woman, ultrasonography at 22+6 gestational weeks had revealed abnormal fetal heart development and ectopic pulmonary vein drainage. G-banded karyotyping showed that the fetus has a karyotype of mos 47,XX,+12[1]/46,XX[73], with the mosaicism rate being 1.35%. CMA results suggested that about 18% of fetal chromosome 12 was trisomic. A newborn was delivered at 39 weeks of gestation. Follow-up confirmed severe congenital heart disease, small head circumference, low-set ears and auricular deformity. The infant had died 3 months later. The database search has retrieved 9 reports. Literature review suggested that the liveborn infants with mosaic trisomy 12 had diverse clinical manifestations depending on the affected organs, which had included congenital heart disease and/or other organs and facial dysmorphisms, resulting in adverse pregnancy outcomes.@*CONCLUSION@#Trisomy 12 mosaicism is an important factor for severe heart defects. The results of ultrasound examination have important value for evaluating the prognosis of the affected fetuses.

Genetic analysis and reproductive intervention of 7 families with gonadal mosaicism for Duchenne muscular dystrophy / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for 7 families with gonadal mosaicism for Duchenne muscular dystrophy (DMD).@*METHODS@#For the 7 families presented at the CITIC Xiangya Reproductive and Genetic Hospital from September 2014 to March 2022, clinical data were collected. Preimplantation genetic testing for monogenic disorders (PGT-M) was carried out for the mother of the proband from family 6. Peripheral venous blood samples of the probands, their mothers and other patients from the families, amniotic fluid samples from families 1 ~ 4 and biopsied cells of embryos cultured in vitro from family 6 were collected for the extraction of genomic DNA. Multiplex ligation-dependent probe amplification (MLPA) was carried out for the DMD gene, and short tandem repeat (STR)/single nucleotide polymorphism (SNP)-based haplotypes were constructed for the probands, other patients, fetuses and embryos.@*RESULTS@#The results of MLPA showed that the probands and the fetuses/probands' brothers in families 1 ~ 4, 5, 7 had carried the same DMD gene variants, whilst the probands' mothers were all normal. The proband in family 6 carried the same DMD gene variant with only 1 embryo (9 in total) cultured in vitro, and the DMD gene of the proband's mother and the fetus obtained through the PGT-M were normal. STR-based haplotype analysis showed that the probands and the fetuses/probands' brothers in families 1 ~ 3 and 5 have inherited the same maternal X chromosome. SNP-based haplotype analysis showed that the proband from family 6 has inherited the same maternal X chromosome with only 1 embryo (9 in total) cultured in vitro. The fetuses in families 1 and 6 (via PGT-M) were both confirmed to be healthy by follow up, whilst the mothers from families 2 and 3 had chosen induced labor.@*CONCLUSION@#Haplotype analysis based on STR/SNP is an effective method for judging gonad mosaicism. Gonad mosaicisms should be suspected for women who have given births to children with DMD gene variants but with a normal peripheral blood genotype. Prenatal diagnosis and reproductive intervention may be adapted to reduce the births of further affected children in such families.

A case of a 45,X,46,X+mar male phenotype mosaic Turner syndrome with a mixed gonadal germ cell tumor / Philippine Journal of Obstetrics and Gynecology

@#Turner syndrome is a congenital condition affecting 1 in every 2500 female live births. This condition is characterized by complete or partial loss of the X chromosome. They commonly present with normal female external and internal genitalia and may develop hypogonadism and streak ovaries later in life. We describe an unusual presentation of a case of Turner syndrome – a 31-year-old Filipino with male phenotype mosaic Turner syndrome, with 46,X,+mar[46]/45,X[4] chromosome, presenting with ambiguous genitalia and a pelvoabdominal mass. The patient underwent exploratory laparotomy, peritoneal fluid cytology, adhesiolysis, tumor debulking (gonadectomy) appendectomy, omentectomy, identification and inspection of bilateral ureters and bladder, gonioscopy and biopsy of the urogenital cavity (bladder vs. vagina). Histopathology revealed a mixed gonadal tumor, consisting of 70% yolk sac tumor, and 30% dysgerminoma. The patient eventually succumbed to postoperative complications. Postmortem fluorescence-in situ hybridization revealed a 46,X,+mar[46]/45,X,[4].ish der (Y) (DYZ3+), a marker of chromosome Y origin, consistent with a mosaic type Turner syndrome, associated with increased risk for gonadal malignancy.

Comparison of detection rates of chromosome G-banding karyotype analysis and fluorescence in situ hybridization among children with sex chromosome mosaicisms / 中华医学遗传学杂志

OBJECTIVE@#To explore the coincidence rate of G-banding karyotype analysis and fluorescence in situ hybridization (FISH) for the diagnosis of children with sex chromosome mosaicisms.@*METHODS@#A retrospective analysis was carried out for 157 children with suspected sex chromosome abnormalities who had presented at Shenzhen Children's Hospital from April 2021 to May 2022. Interphase sex chromosome FISH and G-banding karyotyping results were collected. The coincidence rate of the two methods in children with sex chromosome mosaicisms was compared.@*RESULTS@#The detection rates of G-banding karyotype analysis and FISH were 26.1% (41/157) and 22.9% (36/157) , respectively (P > 0.05). The results of G-banding karyotype analysis showed that 141 cases (89.8%) were in the sex chromosome homogeneity group, of which only 5 cases (3.5%) were inconsistent with the results of FISH. There were 16 cases (10.2%) in the sex chromosome mosaicism group, of which 11 cases (68.8%) were inconsistent with the results of FISH. There was a statistical difference between the two groups in the coincidence rate of the results of the two methods (P < 0.05).@*CONCLUSION@#No significant difference was found between G-banding karyotype analysis and FISH in the detection rate of chromosome abnormalities. The coincidence rate in the mosaicism group was lower than that in the homogeneity group, and the difference was statistically significant. The two methods should be combined for clinical diagnosis.

Genetic analysis of a child with mosaicism Turner syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic characteristics of a child with mosaicism Turner syndrome.@*METHODS@#A child who had presented at Linyi People's Hospital on May 19, 2022 due to short stature was selected as the study subject. The child was subjected to combined chromosomal karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA).@*RESULTS@#The child was found to have a 46,X,i(X)(q10)[94]/45,X[6] karyotype. The result of FISH was nucish(XYpter,XYqter)1[78]/(XYpter)1,(XYqter)3[122]. CMA result for her peripheral blood sample was arr[hg19]Xp22.33p11.1(168551_58526888)×1, and that for her oral mucosal cells was arr[hg19]Xp22.33p11.1(168551_58526888)1-2,Xq11.2q28(63000001_155233098)×2-3. By integrating the above findings, her molecular karyotype was determined as mos 46,X,i(X)(q10)[94]/45,X[6].arr[hg19]Xp22.33p11.1(168551_58526888)×1-2,Xq11.2q28(63000001_155233098)×2-3.nucish(XYpter)1,(XYqter)3[122]/(XYpter,XYqter)1[78], which has indicated mosaicism Turner syndrome.@*CONCLUSION@#The 46,X,i(X)(q10)/45,X mosaicism probably underlay the pathogenesis in this child.

Study of a fetus with confined placental mosaicism for trisomy 2 in conjunct with fetal uniparental disomy and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic analysis for a fetus with confined placental mosaicism (CPM) for trisomy 2 (T2) in conjunct with fetal uniparental disomy (UPD).@*METHODS@#Amniocentesis and chromosomal karyotyping was carried out for a pregnant woman with a high risk for chromosome 2 anomalies indicated by non-invasive prenatal testing (NIPT). Single nucleotide polymorphism array (SNP-array) and trio-whole exome sequencing (Trio-WES) were carried out. Ultrasonography was used to closely monitor the fetal growth. Multifocal sampling of the placenta was performed after delivery for copy number variation sequencing (CNV-seq).@*RESULTS@#The fetus was found to have a normal chromosomal karyotype. SNP-array has revealed multiple regions with loss of heterozygosity (LOH) on chromosome 2. Trio-WES confirmed the presence of maternal UPD for chromosome 2. Ultrasonography has revealed intrauterine growth restriction and oligohydramnios. Intrauterine fetal demise had occurred at 23+4 weeks of gestation. Pathological examination had failed to find salient visceral abnormality. The placenta was proved to contain complete T2 by CNV-seq.@*CONCLUSION@#T2 CPM can cause false positive result for NIPT and may be complicated with fetal UPD, leading to adverse obstetric outcomes such as intrauterine growth restriction, oligohydramnios and intrauterine fetal demise.

Genetic analysis of a rare case with Disorder of sex development due to structural rearrangement of Y chromosome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a rare case with Disorder of sex development.@*METHODS@#Clinical data of the patient was collected. Chromosomal karyotyping, SRY gene testing, whole exome sequencing (WES), low-coverage massively parallel copy number variation sequencing (CNV-seq), fluorescence in situ hybridization (FISH), and whole genome sequencing (WGS) were carried out.@*RESULTS@#The patient, a 14-year-old female, had manifested short stature and dysplasia of second sex characteristics. She was found to have a 46,XY karyotype and positive for the SRY gene. No pathogenic variant was found by WES, except a duplication at Yp11.32q12. The result of CNV-seq was 47,XYY. FISH has confirmed mosaicism for a dicentric Y chromosome. A 23.66 Mb duplication on Yp11.32q11.223 and a 5.16 Mb deletion on Yq11.223q11.23 were found by WGS. The breakpoint was mapped at chrY: 23656267. The patient's karyotype was ultimately determined as 46,X,psu idic(Y)(q11.223)/46,X,del(Y)(q11.223).@*CONCLUSION@#The combination of multiple methods has facilitated clarification of the genetic etiology in this patient, which has provided a reference for the clinical diagnosis and treatment.

Genetic analysis of a fetus with mosaicism Y chromosome aberration / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal diagnosis for a fetus with mosaicism Yq deletion.@*METHODS@#A fetus with high risk of sex chromosomes indicated by non-invasive prenatal testing (NIPT) at Tianjin Medical University General Hospital in July 2021 was selected as the study subject. Prenatal diagnosis of the fetus was performed with combined G-banded chromosomal karyotyping, fluorescence in situ hybridization (FISH), copy number variation sequencing (CNV-seq), real-time fluorescence PCR (QF-PCR), and ultrasound examination.@*RESULTS@#Analysis of the amniocytes at 23 gestational weeks had yielded a 45,X karyotype. However, FISH had shown signals of Y chromosome. Re-examination by cordocentesis had shown a mosaicism of 46,X,+mar[33]/45,X[17]. FISH showed that 69% of the cells had contained Y chromosome signals. The result of CNV-seq was seq[19]del(Y)(q11.1q12)(mos) chrY: g.13200001_ 28820000del (mosaicism rate = 64%), which suggested mosaicism for a Yq deletion, which encompassed the azoospermia factor (AZF) region. Deletion of the AZF region was verified by QF-PCR. The fetal karyotype was ultimately determined as mos46,X,del(Y)(q11.1)[33]/45,X[17]. Although ultrasound examination had shown no abnormality in the fetus, the couple had opted to terminate the pregnancy, and the induced fetus had a normal male appearance.@*CONCLUSION@#The combined use of multiple techniques is beneficial for accurate and rapid prenatal diagnosis. For fetuses with mosaicism chromosomal abnormalities, it may be difficult to accurately predict the postnatal phenotype. It is therefore necessary to further explore their genotype-phenotype correlation in order to provide better guidance upon genetic counseling.

Delineation of a mosaicism fetal supernumerary marker chromosome with combined genetic techniques / 中华医学遗传学杂志

OBJECTIVE@#To delineate the origin and content of a mosaicism small supernumerary marker chromosome (sSMC) in a fetus with combined chromosomal karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH).@*METHODS@#The fetus of a 31-year-old pregnant woman who had presented at the Maternal and Child Health Care Hospital of Longhua District of Shenzhen City in 2022 was selected as the study subject. Non-invasive prenatal testing suggested that the fetus has harbored a 8.75 Mb duplication in 4q12q13.1. With informed consent, amniotic fluid and peripheral blood samples were taken from the couple for chromosomal karyotyping analysis. The origin and content of a sSMC was identified by CMA, and its proportion in amniotic fluid was determined with a FISH assay.@*RESULTS@#The karyotypes of the pregnant woman, her husband and the fetus were respectively determined as 46,XX, 46,XY,inv(9)(p12q12), and 47,XY,inv(9)(p12q12)pat,+mar[75]/ 46,XY,inv(9)(p12q12)pat[25]. CMA test of the amniotic fluid sample was arr[hg19]4p11q13.1(48978053_63145931)×3, which revealed no mosaicism. However, FISH analysis showed that 59% of interphase cells from the cultured amniotic fluid sample had contained three signals for the centromere of chromosome 4, whilst 65% of interphase cells from the re-sampled amniotic fluid had three such signals, which confirmed the existence of trisomy 8 mosaicism.@*CONCLUSION@#Chromosomal structural abnormality combined with mosaicism can be delineated with combined chromosomal karyotyping and molecular techniques such as FISH and CMA, which has enabled more accurate counseling for the family.

Genetic analysis of an infant death due to a paternally derived FOXF1 somatic-gonadal mosaic variant / 中华医学遗传学杂志

OBJECTIVE@#To investigate the genetic characteristics and cause of death for an infant with alveolar capillary dysplasia and pulmonary vein misalignment (ACD/MPV).@*METHODS@#An infant with ACD/MPV diagnosed at the Affiliated Maternity and Child Health Care Hospital of Nantong University in September 2022 was selected as the study subject. Clinical data of the infant were collected. Whole exome sequencing (WES) was carried out to detect genetic variants in the skin tissue, and Sanger sequencing was performed for verifying the candidate variants in the parents. Droplet digital PCR (ddPCR) was used to determine the mosaicism ratio of the variant in different germ layer-derived samples from the father.@*RESULTS@#The infant had died within 2 days after birth due to hypoxemia and respiratory distress. WES revealed that she has harbored a c.433C>T nonsense variant in exon 1 of the FOXF1 gene, which was unreported previously. Sanger sequencing has verified the variant in the infant, with her mother's locus being the wild-type and a minor variant peak noted in her father. ddPCR indicated that the mosaic ratio of the c.433C>T variant in the father's sperm was 27.18%, with the mosaic ratios of the variant in tissues originating from the three germ layers ranging from 11% to 28%.@*CONCLUSION@#The c.433C>T variant derived from the paternal germline and somatic mosaicism of the FOXF1 gene had probably predisposed to the neonatal death of this infant. ddPCR is an effective method for detecting mosaic variants.

Clinical features and genetic analysis of two fetuses with ring chromosome 21 mosaicism / 中华医学遗传学杂志

OBJECTIVE@#To investigate the perinatal clinical phenotype and genetic characteristics of two fetuses with ring chromosome 21 mosaicisms.@*METHODS@#Two fetuses who were diagnosed at the Xiamen Maternal and Child Health Care Hospital in November 2021 were selected as the study subjects. Clinical data of the two fetuses were collected. Conventional G-banded karyotyping and chromosomal microarray analysis (CMA) were carried out for the fetuses and their parents.@*RESULTS@#Prenatal ultrasonography of fetus 1 has revealed absence of nasal bone, ventricular septal defect, persistent left superior vena cava, and mild tricuspid regurgitation. Chromosomal karyotyping was 46,X?,dic r(21;21)(p12q22;q22p12)[41]/45,X?,-21[9]. CMA has revealed a 30.00 Mb quadruplication at 21q11.2q22.3 and a 3.00 Mb deletion at 21q22.3. For fetus 2, ultrasonography has revealed pointed echo of the nasal bone. The fetus was found to have a karyotype of 46,X?,r(21)(p12q22)[83]/45,X?,-21[14]/46,X?,dic r(21;21)(p12q22;q22p12)[3]. CMA has revealed a 5.10 Mb quadruplication at 21q22.12q22.3 and a 2.30 Mb deletion at 21q22.3.@*CONCLUSION@#The perinatal phenotype of the two fetuses with ring chromosome 21 mosaicisms is related to the duplication of chromosomal segments near the breakpoints of the chromosomal deletions. The combined chromosomal karyotyping and CMA has enabled prenatal diagnosis and genetic counseling for these families.

The value of combined CNV-Seq and chromosomal karyotyping for the detection of amniocytic mosaicisms and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of combined copy number variation sequencing (CNV-seq) and chromosomal karyotyping for the diagnosis of amniocytic mosaicisms, in addition with a literature review.@*METHODS@#Forty cases of amniocytic mosaicisms detected at the Genetic and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2021, in addition with 245 mosaicisms retrieved from 11 recent literature were evaluated in terms of detection rate, consistency rate, and pregnancy outcomes.@*RESULTS@#The detection rate of amniocytic mosaicisms was 0.46% (40/8 621) in our center. And its consistency rate with chromosomal karyotyping was 75.0% (30/40). After genetic counseling, 30 (75.0%) couples had opted to terminate the pregnancy, 5 (12.5%) had decided to continue with the pregnancy, 3 (7.5%) fetuses were born alive, and 2 cases (5.0%) were lost in touch. By contrast, 245 cases (0.39%) of mosaicisms were identified among 63 577 amniotic samples, with a consistency rate of 62.8% (103/164) with other techniques. Among these, 114 cases (55.1%) were terminated, 75 (36.2%) were born alive, and 18 (8.7%) were lost during the follow up.@*CONCLUSION@#Combined CNV-seq and chromosomal karyotyping has a high value for the detection of amniotic mosaicisms.

Application of fluorescence in situ hybridization combined with chromosomal karyotyping analysis in children with disorders of sex development due to sex chromosome abnormalities / 中华医学遗传学杂志

OBJECTIVE@#To retrospectively analyze sex chromosomal abnormalities and clinical manifestations of children with disorders of sex development (DSD).@*METHODS@#A total of 14 857 children with clinical features of DSD including short stature, cryptorchidism, hypospadia, buried penis and developmental delay were recruited from Zhengzhou Children's Hospital from January 2013 to March 2022. Fluorescence in situ hybridization (FISH) and chromosomal karyotyping were carried out for such children.@*RESULTS@#In total 423 children were found to harbor sex chromosome abnormalities, which has yielded a detection rate of 2.85%. There were 327 cases (77.30%) with Turner syndrome and a 45,X karyotype or its mosaicism. Among these, 325 were females with short stature as the main clinical manifestation, 2 were males with short stature, cryptorchidism and hypospadia as the main manifestations. Sixty-two children (14.66%) had a 47,XXY karyotype or its mosaicism, and showed characteristics of Klinefelter syndrome (KS) including cryptorchidism, buried penis and hypospadia. Nineteen cases (4.49%) had sex chromosome mosaicisms (XO/XY), which included 11 females with short stature, 8 males with hypospadia, and 6 cases with cryptorchidism, buried penis, testicular torsion and hypospadia. The remainder 15 cases (3.55%) included 9 children with a XYY karyotype or mosaicisms, with main clinical manifestations including cryptorchidisms and hypospadia, 4 children with a 47,XXX karyotype and clinical manifestations including short stature and labial adhesion, 1 child with a 46,XX/46,XY karyotype and clinical manifestations including micropenis, hypospadia, syndactyly and polydactyly, and 1 case with XXXX syndrome and clinical manifestations including growth retardation.@*CONCLUSION@#Among children with DSD due to sex chromosomal abnormalities, sex chromosome characteristics consistent with Turner syndrome was most common, among which mosaicism (XO/XX) was the commonest. In terms of clinical manifestations, the females mainly featured short stature, while males mainly featured external genital abnormalities. Early diagnosis and treatment are particularly important for improving the quality of life in such children.