Clinical phenotype and genetic analysis of a fetus with Cardiac valvular dysplasia type 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with Cardiac valvular dysplasia type 1 (CVDP1).@*METHODS@#A CVDP1 fetus identified at the Ningbo Women and Children's Hospital on July 7, 2022 was selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were subjected to trio-whole exome sequencing (trio-WES), and candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus had exhibited generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes. Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c.2977C>T (p.R993*) and c.1460G>A (p.W487*), which were respectively inherited from its father and mother. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2977C>T (p.R993*) variant was evaluated to be likely pathogenic (PVS1_Moderate+PM2_Supporting+PM3+PP4), whilst the c.1460G>A (p.W487*) variant was evaluated to be pathogenic (PVS1+PM2_Supporting+PP4).@*CONCLUSION@#The c.2977C>T (p.R993*) and c.1460G>A (p.W487*) compound heterozygous variants of the PLD1 gene probably underlay the CVDP1 in the fetus. Above discovery has enriched the mutational spectrum of the PLD1 gene and provided a guidance for genetic counseling and prenatal diagnosis in this family.

Clinical characteristics and genetic counseling for a three-generation Chinese pedigree with recurrent fetal Kabuki syndrome due to variant of KDM6A gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pregnant woman with a history of adverse pregnancy outcomes.@*METHODS@#A woman with an adverse history of pregnancies including one fetal demise and two induced abortions due to fetal diaphragmatic hernia and complex cardiac anomalies was selected as the study subject. Muscle tissue from the induced abortus was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the couple and other family members.@*RESULTS@#Genetic sequencing revealed that the fetus has harbored a frameshift variant of the KDM6A gene (NM_001291415.2), namely c.1228_1229del (p.Gln410GlufsTer2), which was inherited from the woman and her mother. The variant was unreported previously, and the woman was found to have short stature, sparse eyebrows in the outer third, peculiar facial features, but normal intelligence in addition with female congenital genital malformation, like incomplete vaginal septum, double cervix, double uterus, and unilateral ovary absence. mostly similar phenotypes observed in her mother.@*CONCLUSION@#The hemizygous c.1228_1229del variant of the KDM6A gene probably underlay the abnormalities in the fetus. All findings have enabled genetic counseling for this family featuring X-linked inheritance, and the woman had given birth to a healthy girl with appropriate prevention and intervention.

Resultado a largo plazo de una serie de fetos con agenesia aislada del septum pellucidum / Long-term postnatal outcome of fetuses with isolated agenesis of the septum pellucidum

Objetivo: Reportar el resultado a largo plazo de una serie de fetos con agenesia del septum pellucidum aislada (ASP), con medición de su quiasma óptico mediante neurosonografía fetal (NSG). Método: Se incluyeron todas las pacientes con ASP y NSG evaluadas desde el año 2008 a la fecha y con seguimiento hasta su edad escolar. En todos los casos se consignaron los datos clínicos de NSG y de resonancia magnética (RM), cuando esta se realizó. Se entrevistó telefónicamente a los padres. Resultados: Nueve pacientes cumplieron los criterios: cuatro con displasia septo-óptica (DSO) (rango de seguimiento: 5-14 años) y cinco sin DSO (rango de seguimiento: 7-10 años). Un décimo caso se excluyó por tener solo 6 meses de seguimiento. Ninguna de las ASP tuvo otra anomalía detectada en su seguimiento. Ninguno de los casos con DSO tuvo alteración del tamaño de su quiasma óptico en la NSG ni anormalidad en la vía óptica en la RM. Conclusiones: En nuestra población, el riesgo residual de DSO frente a ASP es del 44,4%. En el seguimiento, nuestra definición de ASP por NSG no tuvo falsos negativos con relación a otras anomalías de aparición posnatal, a excepción de la DSO.

Objective: To report the long-term outcome of a series of fetuses with isolated septum pellucidum agenesis (ASP) with measurement of their optic chiasm by fetal neurosonography (NSG). Method: All patients with ASP and NSG evaluated from 2008 to date and with follow-up until their school age were included. In all cases, clinical, NSG and magnetic resonance imaging (MRI) data were recorded. Parents were interviewed by telephone. Results: Nine patients met the criteria: four with septo-optic dysplasia (SOD) (follow-up range: 5-14 years) and five without SOD (follow-up range: 7-10 years). A tenth case was excluded because only 6 months of follow-up. None of the ASP cases had another anomaly detected in their follow-up. None of the cases with DSO had anomaly of the size of their optic chiasm on NSG or abnormality in the optical pathway in the MRI. Conclusions: In our population, the residual risk of DSO versus ASP is 44.4%. At follow-up, our NSG definition of ASP had no false negatives in relation to other postnatal-onset anomalies, except for SOD.

É preciso um pacto para erradicar a sífilis congênita no Estado do Rio de Janeiro / A pact is needed to eradicate congenital syphilis in the State of Rio de Janeiro

Os números mostram que os municípios do Rio de Janeiro não têm conseguido diagnosticar precisamente ou tratado adequadamente suas gestantes, resultando na infecção e mortes de bebês. A transmissão vertical é de 70 a 100% dos casos, com morte de 40% doas fetos. A sífilis congênita é a mais antiga infecção congênita e a primeira pandemia com tratamento disponível no SUS, mas persiste por falta de diagnóstico e tratamento oportuno. Os casos de sífilis congênita atesta que falta qualidade às consultas. É preciso implementar esse pacto de ações na comissão Intergestores Bipartite do Rio de Janeiro: cabe à Secretaria de Estado articular com os secretários municipais o delineamento da política pública e sua implementação. (AU)

Revisión Exploratoria: Comunicación de la Articulación Temporomandibular y del Oído Medio en Fetos y Niños / Exploratory Review: Temporomandibular Joint and Middle Ear Communication in Fetuses and Infants

La Articulación temporomandibular (ATM) cumple funciones importantes para la vida; su adecuado funcionamiento se puede alterar por trastornos temporomandibulares (TTM). La sintomatología de los TTM es variada, entre ellos se encuentra dolor en los músculos masticatorios, ruidos articulares y con menos frecuencia algunos pacientes refieren síntomas auditivos, lo que sugiere la existencia de una relación entre la ATM y el oído medio; sin embargo, esta relación no es clara. En consecuencia, el presente estudio tiene como propósito realizar una revisión de literatura para identificar los aspectos conocidos, desconocidos y controvertidos sobre la relación entre la ATM y el oído medio en niños y fetos. Se efectuó una búsqueda de la literatura en bases de datos utilizando los operadores booleanos (AND/OR) y los términos clave en inglés y en español. Se identificaron inicialmente 1080 artículos, se eliminaron los artículos duplicados y se aplicaron los criterios de inclusión y exclusión. Finalmente, se seleccionaron un total de 14 artículos que se revisaron a texto completo. Los estudios encontrados se enfocan en el desarrollo histoembriológico de la ATM y cómo ese desarrollo se da en conjunto con los componentes del oído medio. Adicionalmente, se identificaron investigaciones sobre el origen, la morfología y función del ligamento discomaleolar, el ligamento esfenomandibular y la fisura petrotimpánica como estructuras que conectan la ATM y el oído medio, pero los resultados han sido controvertidos. Se concluye que son necesarios más estudios para determinar cualquier relación anatómica y fisiológica que pueda existir entre la ATM y el sistema auditivo en fetos y niños.

SUMMARY: The temporomandibular joint (TMJ) has important functions for life; its proper functioning can be altered by temporomandibular disorders (TMD). The symptomatology of TMD is varied, including pain in the masticatory muscles, joint noises and less frequently some patients report auditory symptoms, suggesting the existence of a relationship between the TMJ and the middle ear; however, this relationship is not clear. Consequently, the present study aims to conduct a literature review to identify the known, unknown and controversial aspects of the relationship between TMJ and the middle ear in children and fetuses. A literature search was performed in databases using Boolean operators (AND/ OR) and key terms in English and Spanish. A total of 1080 articles were initially identified; duplicate articles were eliminated and inclusion and exclusion criteria were applied. Finally, a total of 14 articles were selected and reviewed in full text. The studies found focus on the histoembryological development of the TMJ and how that development occurs in conjunction with the middle ear components. Additionally, research on the origin, morphology, and function of the discomalleolar ligament, sphenomandibular ligament, and petrotympanic fissure as structures connecting the TMJ and middle ear was identified, but the results have been controversial. It is concluded that further studies are necessary to determine any anatomical and physiological relationship that may exist between the TMJ and the auditory system in fetuses and children.

Dissecação anatômica como estratégia para o estudo do sistema neural em fetos humanos / Anatomic dissection as a strategy for the study of the neural system in fetuses / Disección anatómica como estrategia para el estudio del sistema neural en fetos

Esse trabalho busca relatar o processo de confecção de peças anatômicas para o ensino da anatomia humana a partir de material cadavérico fetal. Os discentes do curso de medicina da Universidade Federal do Paraná (UFPR) ­ Campus Toledo participaram do programa de voluntariado acadêmico e deram atenção especial aos aspectos técnicos do processo de dissecação, bem como a experiência subjetiva desse procedimento como ferramenta de aprendizado ativo. O procedimento foi realizado na sala de preparação de cadáver da UFPR ­ Campus Toledo, utilizando instrumental de dissecação e cadáveres humanos fetais com 20, 17 e 14 semanas de idade gestacional, direcionado de modo a expor as partes constituintes do sistema neural. Foram confeccionadas peças de cérebro, cerebelo, tronco encefálico, medula espinal, nervos espinais e suas estruturas associadas. Os voluntários envolvidos foram capazes de produzir material de estudo de qualidade através da dissecação e fortalecer seu conhecimento em anatomia humana e aptidão manual. Também foi dada atenção à importância e às limitações do processo de dissecação como estratégia de aprendizado em cursos da área de saúde. pôde ser observado que a dissecação pode fazer parte de uma formação completa e bem estruturada dos discentes, que por sua vez irão integrar a sociedade e a academia. Além disso, a exposição da topografia neural fetal pode servir de referencial para posteriores estudos que venham a utilizar essas informações.

This work aims to report the confection process of anatomic pieces for teaching human anatomy from fetal cadaveric material. The students of the medicine course of Universidade Federal do Paraná (UFPR) ­ Campus Toledo, took part in the academic volunteer program and paid special attention to the technical aspects of the dissection process, as well as the subjective experience of this procedure as an active learning tool. The procedure was performed at the cadaver preparation room of the UFPR ­ Campus Toledo, using dissection tools and human fetal corpses of 20, 17 and 14 weeks of gestational ages, directed so as to expose the constituent parts of the neural system. Pieces of the brain, cerebellum, brainstem, spinal cord, spinal nerves, and its associated structures were made. The involved voluntaries were able to produce quality study material through dissection, and strengthen their knowledge in human anatomy and manual skill. Attention was also given to the importance and limitations of the dissection process as a learning strategy in health courses. it was observed that dissection can be part of a complete and well-structured training of students, who in turn will integrate society and academia. In addition, the exposure of fetal neural topography can serve as a reference for further studies that use this information

Este trabajo tiene como objetivo relatar el proceso de confección de piezas anatómicas para la enseñanza de la anatomía humana a partir de material cadavérico fetal. Los alumnos del curso de medicina de la Universidade Federal do Paraná (UFPR) - Campus Toledo, participaron del programa de voluntariado académico y prestaron especial atención a los aspectos técnicos del proceso de disección, así como a la vivencia subjetiva de este procedimiento como herramienta de aprendizaje activo. El procedimiento fue realizado en la sala de preparación de cadáveres de la UFPR - Campus Toledo, utilizando herramientas de disección y cadáveres de fetos humanos de 20, 17 y 14 semanas de edad gestacional, dirigidos de forma a exponer las partes constitutivas del sistema neural. Se realizaron piezas del cerebro, cerebelo, tronco encefálico, médula espinal, nervios espinales y sus estructuras asociadas. Los voluntarios participantes pudieron elaborar material de estudio de calidad mediante la disección y reforzar sus conocimientos de anatomía humana y habilidad manual. También se prestó atención a la importancia y las limitaciones del proceso de disección como estrategia de aprendizaje en los cursos de salud. Se observó que la disección puede formar parte de una formación completa y bien estructurada de los estudiantes, que a su vez integrarán la sociedad y el mundo académico. Además, la exposición de la topografía neural fetal puede servir de referencia para estudios posteriores que utilicen esta información.

Analysis of COL1A1 and COL1A2 gene variants in two fetuses with osteogenesis imperfecta / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of two fetuses with an osteogenesis imperfecta (OI) phenotype.@*METHODS@#Two fetuses diagnosed at the Affiliated Hospital of Weifang Medical College respectively on June 11, 2021 and October 16, 2021 were selected as the study subjects. Clinical data of the fetuses were collected. Amniotic fluid samples of the fetuses and peripheral blood samples of their pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing (WES) and Sanger sequencing were carried out to identify the candidate variants. Minigene splicing reporter analysis was used to validate the variant which may affect the pre-mRNA splicing.@*RESULTS@#For fetus 1, ultrasonography at 17+6 weeks of gestation had revealed shortening of bilateral humerus and femurs by more than two weeks, in addition with multiple fractures and angular deformities of long bones. WES revealed that fetus 1 had harbored a heterozygous c.3949_3950insGGCATGT (p.N1317Rfs*114) variant in exon 49 of the COL1A1 gene (NM_000088.4). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was classified as a pathogenic variant (PVS1+PS2+PM2_Supporting) for disrupting the downstream open reading frame resulting in premature translational termination, being de novo in origin, and lacking records in the population and disease databases.For fetus 2, ultrasonography at 23 weeks of gestation also revealed shortening of bilateral humerus and femurs by one and four weeks, respectively, in addition with bending of bilateral femurs, tibias and fibulas. Fetus 2 had harbored a heterozygous c.1557+3A>G variant in intron 26 of the COL1A2 gene (NM_000089.4). Minigene experiment showed that it has induced skipping of exon 26 from the COL1A2 mRNA transcript, resulting in an in-frame deletion (c.1504_1557del) of the COL1A2 mRNA transcript. The variant was inherited from its father and had been previously reported in a family with OI type 4. It was therefore classified as a pathogenic variant (PS3+PM1+PM2_Supporting+PP3+PP5).@*CONCLUSION@#The c.3949_3950insGGCATGT (p.N1317Rfs*114) variant in the COL1A1 gene and c.1557+3A>G variant in the COL1A2 gene probably underlay the disease in the two fetuses. Above findings not only have enriched the mutational spectrum of OI, but also shed light on the correlation between its genotype and phenotype and provided a basis for genetic counseling and prenatal diagnosis for the affected pedigrees.

Genetic analysis of a Chinese family affected with α-dystroglycanopathy due to variant of B3GALNT2 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with recurrent fetal hydrocephalus.@*METHODS@#A couple who had presented at the Affiliated Hospital of Putian College on March 3, 2021 was selected as the study subject. Following elective abortion, fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple, and were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus was found to harbor compound heterozygous variants of the B3GALNT2 gene, namely c.261-2A>G and c.536T>C (p.Leu179Pro), which were inherited from its father and mother, respectively.According to the guidelines of American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM2_Supporting; PM3+PM2_Supporting+PP3+PP4).@*CONCLUSION@#The compound heterozygous variants of the B3GALNT2 gene probably underlay the α-dystroglycanopathy in this fetus. Above results have provided a basis for genetic counseling of this pedigree.

Clinical and genetic analysis of a fetus with 17q12 microdeletion syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic characteristics of a fetus with 17q12 microdeletion syndrome.@*METHODS@#A fetus with 17q12 microdeletion syndrome who was diagnosed at Huzhou Maternal & Child Health Care Hospital in June 2020 was selected as the study subject. Clinical data of the fetus was collected. The fetus was subjected to chromosomal karyotyping and chromosomal microarray analysis (CMA). To determine the origin of fetal chromosomal abnormality, its parents were also subjected to CMA assay. The postnatal phenotype of the fetus was also investigated.@*RESULTS@#Prenatal ultrasound revealed polyhydramnios and fetal renal dysplasia. The fetus was found to have a normal chromosomal karyotype. CMA has detected a 1.9 Mb deletion in the 17q12 region, which has encompassed five OMIM genes including HNF1B, ACACA, ZNHIT3, CCL3L1 and PIGW. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the 17q12 microdeletion was predicted as pathogenic copy number variation (CNV). CMA analysis has detected no pathogenic CNV in both parents. After birth, the child was found to have renal cysts and abnormal brain structure. Combined with the prenatal findings, the child was diagnosed with 17q12 microdeletion syndrome.@*CONCLUSION@#The fetus has 17q12 microdeletion syndrome presenting as abnormalities of the kidney and central nervous system, which are strongly correlated with functional defects of the deletion region involving the HNF1B and other pathogenic genes.

Clinical phenotype and genetic analysis of a fetus with Glutaracidemia type II C / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic variants of a fetus with Glutaracidemia type II C (GA II C).@*METHODS@#Clinical data of a 32-year-old pregnant woman and her fetus with GA II C diagnosed at the Third Affiliated Hospital of Zhengzhou University in December 2021 due to the enlargement and enhanced echo of the kidneys and oligohydramnios fluid at 17 weeks were analyzed retrospectively. Amniotic fluid sample of the fetus and peripheral blood samples of the couple were collected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Copy number variation (CNV) was detected by using low-coverage whole genome sequencing (CNV-seq).@*RESULTS@#At 18 weeks' gestation, ultrasound revealed that the fetus had enlargement and enhanced echo of the kidneys along with no echo of renal parenchymal tubular fissure and oligohydramnios. MRI at 22 weeks' gestation confirmed that both kidneys were enlarged with uniformly increased abnormal T2 signal and decreased DWI signal. The volume of both lungs was small, with slightly higher T2 signal. No CNV was detected in the fetus. WES revealed that the fetus has harbored compound heterozygous variants of the ETFDH gene, namely c.1285+1G＞A and c.343_344delTC, which were inherited from its father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PM2_Supporting+PS3_Supporting; PVS1+PM2_Supporting+PM3).@*CONCLUSION@#The c.1285+1G＞A and c.343_344delTC compound heterozygous variants of the ETFDH gene probably underlay the disease in this fetus. Type II C glutaric acidemia may manifest as bilateral kidney enlargement with enhanced echo and oligohydramnios. Discovery of the c.343_344delTC has enriched the spectrum of ETFDH gene variants.

Genetic analysis of a fetus with de novo 46,X,der(X)t(X;Y)(q26;q11) / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal genetic testing for a fetus with de novo 46,X,der(X)t(X;Y)(q26;q11).@*METHODS@#A pregnant woman who had visited the Birth Health Clinic of Lianyungang Maternal and Child Health Care Hospital on May 22, 2021 was selected as the study subject. Clinical data of the woman was collected. Peripheral blood samples of the woman and her husband and umbilical cord blood of the fetus were collected and subjected to conventional G-banded chromosomal karyotyping analysis. Fetal DNA was also extracted from amniotic fluid sample and subjected to chromosomal microarray analysis (CMA).@*RESULTS@#For the pregnant women, ultrasonography at 25th gestational week had revealed permanent left superior vena cava and mild mitral and tricuspid regurgitation. G-banded karyotyping analysis showed that the pter-q11 segment of the fetal Y chromosome was connected to the Xq26 of the X chromosome, suggesting a Xq-Yq reciprocal translocation. No obvious chromosomal abnormality was found in the pregnant woman and her husband. The CMA results showed that there was approximately 21 Mb loss of heterozygosity at the end of the long arm of the fetal X chromosome [arr [hg19] Xq26.3q28(133912218_154941869)×1], and 42 Mb duplication at the end of the long arm of the Y chromosome [arr [hg19] Yq11.221qter(17405918_59032809)×1]. Combined with the search results of DGV, OMIM, DECIPHER, ClinGen and PubMed databases, and based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the deletion of arr[hg19] Xq26.3q28(133912218_154941869)×1 region was rated as pathogenic, and the duplication of arr[hg19] Yq11.221qter(17405918_59032809)×1 region was rated as variant of uncertain significance.@*CONCLUSION@#The Xq-Yq reciprocal translocation probably underlay the ultrasonographic anomalies in this fetus, and may lead to premature ovarian insufficiency and developmental delay after birth. Combined G-banded karyotyping analysis and CMA can determine the type and origin of fetal chromosomal structural abnormalities as well as distinguish balanced and unbalanced translocations, which has important reference value for the ongoing pregnancy.

Clinical characteristics and genetic analysis of a fetus with Melnick-Needles syndrome due to variant of FLNA gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a fetus with Melnick-Needles syndrome (MNS).@*METHODS@#A fetus with MNS diagnosed at Ningbo Women and Children's Hospital in November 2020 was selected as the study subject. Clinical data was collected. Pathogenic variant was screened by using trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasonography of the fetus had shown multiple anomalies including intrauterine growth retardation, bilateral femur curvature, omphalocele, single umbilical artery, and oligohydramnios. Trio-WES revealed that the fetus has harbored hemizygous c.3562G>A (p.A1188T) missense variant of the FLNA gene. Sanger sequencing confirmed that the variant was maternally derived, whilst its father was of a wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4).@*CONCLUSION@#The hemizygous c.3562G>A (p.A1188T) variant of the FLNA gene probably underlay the structural abnormalities in this fetus. Genetic testing can facilitate accurate diagnosis of MNS and provide a basis for genetic counseling for this family.

Prenatal diagnosis for a fetus with Walker-Warburg syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a fetus with Walker-Warburg syndrome(WWS).@*METHODS@#A fetus with WWS diagnosed at Gansu Provincial Maternity and Child Health Care Hospital in June 9, 2021 was selected as the study subject. Genomic DNA was extracted from amniotic fluid sample of the fetus and peripheral blood samples from its parents. Trio-Whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus was found to harbor compound heterozygous variants of the POMT2 gene, namely c.471delC (p.F158Lfs*42) and c.1975C>T (p.R659W), which were respectively inherited from its father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), they were respectively rated as pathogenic (PVS1+PM2_Supporting+PP4) and likely pathogenic (PM2_Supporting+PM3+PP3_Moderate+PP4).@*CONCLUSION@#Trio-WES may be used for the prenatal diagnosis of WWS. The compound heterozygous variants of the POMT2 gene probably underlay the disorder in this fetus. Above finding has expanded the mutational spectrum of the POMT2 gene and enabled definite diagnosis and genetic counseling for the family.

Analysis of clinical phenotype and pathogenic variant of a fetus with Cornelia de Lange syndrome type II / 中华医学遗传学杂志

OBJECTIVE@#To explore the prenatal ultrasonographic features and genetic basis for an abortus suspected for type II Cornelia de Lange syndrome (CdLS2).@*METHODS@#A fetus diagnosed with CdLS2 at the Shengjing Hospital Affiliated to China Medical University on September 3, 2019 was selected as the study subject. Clinical data of the fetus and family history was collected. Following induced labor, whole exome sequencing was carried out on the abortus. Candidate variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Prenatal ultrasonography (33 weeks of pregnancy) has revealed multiple anomalies in the fetus, which included slightly widened cavity of septum pellucidum, blurred corpus callosum, slightly reduced frontal lobe volume, thin cortex, fusion of lateral ventricles, polyhydramnios, small stomach bubble, and digestive tract atresia. Whole exome sequencing has revealed a heterozygous c.2076delA (p.Lys692Asnfs*27) frameshifting variant in the SMC1A gene, which was found in neither parent and was rated as pathogenic based on the guidelines of American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The CdLS2 in this fetus may be attributed to the c.2076delA variant of the SMC1A gene. Above finding has provided a basis for genetic counseling and assessment of reproductive risk for this family.

Analysis of MYRF gene variant in a fetus with Cardiac-urogenital syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with Cardiac-urogenital syndrome (CUGS).@*METHODS@#A fetus with congenital heart disease identified at the Maternal Fetal Medical Center for Fetal Heart Disease, Beijing Anzhen Hospital Affiliated to Capital Medical University in January 2019 was selected as the study subject. Clinical data of the fetus was collected. Copy number variation sequencing (CNV-seq) and trio-whole exome sequencing (trio-WES) were carried out for the fetus and its parents. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Detailed fetal echocardiographic examination had revealed hypoplastic aortic arch. The results of trio-WES revealed that the fetus has harbored a de novo splice variant of the MYRF gene (c.1792-2A>C), for which both parents were of the wild-type. Sanger sequencing confirmed the variant to be de novo. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic. CNV-seq has identified no chromosomal anomalies. And the fetus was diagnosed with Cardiac-urogenital syndrome.@*CONCLUSION@#The de novo splice variant of the MYRF gene probably underlay the abnormal phenotype in the fetus. Above finding has enriched the spectrum of MYRF gene variants.

Clinical analysis of monochorionic-diamniotic twins with genetic discordance / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of 5 cases of monochorionic-diamniotic (MCDA) with genetic discordance.@*METHODS@#148 cases of MCDA twins who were diagnosed by amniocentesis at the Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region from January 2016 to June 2020 were selected as the study subjects. Relevant clinical data of the pregnant women were collected, and amniotic fluid samples of the twins were collected separately. Chromosomal karyotyping analysis and single nucleotide polymorphism array (SNP array) assay were carried out.@*RESULTS@#The results of chromosomal karyotyping analysis showed that 5 of the MCDA twins had inconsistent chromosome karyotypes, with an incidence of 3.4% (5/148). SNP array assay showed that 3 fetuses were mosaics.@*CONCLUSION@#Genetic discordance occurs among MCDA twins, and prenatal counseling for such cases should be given by doctors with experience in medical genetics and fetal medicine, and personalized clinical management should be recommended.

Comparison of results of prenatal diagnosis by different techniques for fetuses with increased nuchal translucency / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of chromosomal microarray analysis (CMA) and trio-whole exome sequencing (trio-WES) for fetuses with increased nuchal translucency (NT) thickness.@*METHODS@#Sixty two pregnant women who had visited Urumqi Maternal and Child Care Health Hospital between June 2018 and June 2020 for NT ≥ 3.0 mm at 11 ~ 13+6 gestational weeks were selected as study subjects. Relevant clinical data were collected. The patients were divided into 3.0 ~ ＜3.5 mm (n = 33) and ≥3.5 mm groups (n = 29). Chromosome karyotyping analysis and chromosomal microarray analysis were carried out. And trio-WES analysis was performed on 15 samples with NT thickening but negative CMA results. The distribution and incidence of chromosomal abnormalities in the two groups were compared by using chi-square test.@*RESULTS@#The median age of the pregnant women was 29 years old (22 ~ 41 years old), the median thickness of NT was 3.4 mm (3.0 ~ 9.1 mm), and the median gestational age at the detection was 13+4 weeks (11+5 ~ 13+6 weeks). Chromosome karyotyping analysis has detected 12 cases of aneuploidies and 1 case of derivative chromosome. The detection rate was 20.97% (13/62). CMA has detected 12 cases of aneuploidies, 1 case of pathogenic CNV and 5 cases of variant of uncertain significance (VUS), with a detection rate of 29.03% (18/62). The aneuploidy rate for the NT ≥ 3.5 mm group was higher than that for the 3.0 ≤ NT < 3.5 mm group [3.03% (1/33) vs. 41.38% (12/29), χ² = 13.698, P < 0.001]. There was no statistically significant difference between the two groups in the detection rate of fetal pathogenic CNV and VUS (χ² = 0.028, P > 0.05). Trio-WES analysis of 15 samples with negative CMA result and no structural abnormality has identified 6 heterozygous variants, including SOS1: c.3542C>T (p.A1181V) and c.3817C>G (p.L1273V), COL2A1: c.436C>T (p.P146S) and c.3700G>A (p.D1234N), LZTR1: c.1496T>C (p.V499A), and BRAF: c.64G>A (p.D22N), respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), all of the variants were rated as VUS.@*CONCLUSION@#NT thickening can indicate chromosome abnormality, and CMA and trio-WES may be used for the prenatal diagnosis.

Prenatal diagnosis and pregnancy outcome of fetuses with rare autosomal trisomies indicated by non-invasive prenatal testing / 中华医学遗传学杂志

OBJECTIVE@#To analyze the result of prenatal diagnosis and outcome of pregnancy for fetuses with rare autosomal trisomies (RATs) suggested by non-invasive prenatal testing (NIPT).@*METHODS@#A total of 69 608 pregnant women who underwent NIPT at Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University from January 2016 to December 2020 were selected as study subjects. The result of prenatal diagnosis and outcome of pregnancy for those with a high risk for RATs were retrospectively analyzed.@*RESULTS@#Among the 69 608 pregnant women, the positive rate of NIPT for high-risk RATs was 0.23% (161/69 608), with trisomy 7 (17.4%, 28/161) and trisomy 8 (12.4%, 20/161) being the most common, and trisomy 17 (0.6%, 1/161) being the rarest. For 98 women who had accepted invasive prenatal diagnosis, 12 fetal chromosomal abnormalities were confirmed, and in 5 cases the results were consistent with those of NIPT, which yielded a positive predictive value of 5.26%. Among the 161 women with a high risk for RATs, 153 (95%) were successfully followed up. 139 fetuses were ultimately born, with only one being clinically abnormal.@*CONCLUSION@#Most women with a high risk for RATs by NIPT have good pregnancy outcomes. Invasive prenatal diagnosis or serial ultrasonography to monitor fetal growth, instead of direct termination of pregnancy, is recommended.

Prenatal genetic analysis of a fetus with Miller-Dieker syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for fetus with bilateral lateral ventriculomegaly.@*METHODS@#Fetus umbilical cord blood and peripheral blood samples of its parents were collected. The fetus was subjected to chromosomal karyotyping, whilst the fetus and its parents were subjected to array comparative genomic hybridization (aCGH). The candidate copy number variation (CNV) were verified by qPCR, Application goldeneye DNA identification system was used to confirm the parental relationship.@*RESULTS@#The fetus was found to have a normal karyotype. aCGH analysis indicated that it has carried a 1.16 Mb deletion at 17p13.3, which partially overlapped with the critical region of Miller-Dieker syndrome (MDS), in addition with a 1.33 Mb deletion at 17p12 region, which is associated with hereditary stress-susceptible peripheral neuropathy (HNPP). Its mother was also found to harbor the 1.33 Mb deletion at 17p12. qPCR analysis confirmed that the expression levels of genes from the 17p13.3 and 17p12 regions were about the half of that in the normal control, as well as the maternal peripheral blood sample. Parental relationship was confirmed between the fetus and its parents. Following genetic counseling, the parents has chosen to continue with the pregnancy.@*CONCLUSION@#The fetus was diagnosed with Miller-Dieker syndrome due to the de novo deletion at 17p13.3. Ventriculomegaly may be an important indicator for prenatal ultrasonography in fetuses with MDS.