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Unstable hemoglobin (Hb) variants are a rare cause of congenital hemolytic anemia. We describe a Chinese girl who presented with transfusion-dependent anemia in early infancy. Her diagnosis of Hb Calgary [β64(E8)Gly > Val; HBB :c.194G > T] was not made until molecular testing was performed at the age of 5 years. Our case highlights the importance of early genetic testing in order to make the diagnosis, which may not only be useful for patient management and family counseling, but also for avoiding further unnecessary investigative attempts.

A series of novel substituted uracil-1'( N )-acetic acid esters ( 5 - 9 ) and 4-pyridone-1'( N )-acetic acid esters ( 10 - 11 ) of 20(S)-camptothecins (CPTs) have been synthesized by the acylation method. All of these new esters were assayed for in vitro cytotoxicity against five human cancer cell lines A549, Bel7402, BGC-823, HCT-8 and A2780. The in vitro bioassay results showed that all the synthesized compounds 5 - 11 had cytotoxities that were higher than TPT and comparable to CPT on these five tumor cell lines, some of them even showed comparable or superior cytotoxic activity to CPT. The in vitro data exhibited the cytotoxicity of the ester depended on that of its parent compound. The ester 5 , 6 , 8 , 10 , 11 even possessed the cytotoxity activity comparable to or even a little better than CPT on A549, HCT-8 and A2780. The compound 11 had the same level of cytoxity on Bel7402 as that of CPT. Here the synthesis and the in vitro antitumor evaluation of a series of novel 20- O -linked substituted uracil-1'( N )-acetic acid and 4-pyridone-1'( N )-acetic acid esters derivatives of CPTs are reported.

Patients with the genotype of β 0 /β 0 for β-thalassemia (β-thal) usually behave as β-thal major (β-TM) phenotype which is transfusion-dependent. The pathophysiology of β-thal is the imbalance between α/β-globin chains. The degree of α/β-globin imbalance can be reduced by the more effective synthesis of γ-globin chains, and increased Hb F levels, modifying clinical severity of β-TM. We report a Chinese child who had homozygous β 0 -thal and a heterozygous KLF1 mutation. The patient had a moderate anemia since 6 months old, keeping a baseline Hb value of 8.0-9.0 g/dL. She had normal development except for a short stature (3rd percentile) until 6 years old, when splenomegaly and facial bone deformities occurred. Although genetic alteration of KLF1 expression in β 0 /β 0 patients can result in some degree of disease alleviation, our case shows that it is insufficient to ameliorate satisfactorily the presentation. This point should be borne in mind for physicians who provide the genetic counseling and prenatal diagnosis to at-risk families.

We report three cases of fetalis hydrops associated with nondeletional α-thalassemia. Two cases were caused by hemoglobin (Hb) H-Quong Sz disease, and one caused by homozygous Hb Constant Spring. Fetal hydrops occurred in the late second trimester in all three cases. Our study indicates that for pregnancies at risk for fetal nondeletional Hb H disease, strict ultrasound follow-up is particularly important. Even without techniques of intrauterine transfusion treatment, early prenatal diagnosis can enable parents to make timely decisions.

We identified a novel mutation in the SUPT5H gene in a Chinese female who presented with a β-thalassemia trait. The substitution of c.193C > T (p.Arg65*) leads to a premature stop codon on residue 65 and could be associated with haploinsufficiency. This variant was inherited from the mother who also had the asymptomatic phenotype of β-thalassemia trait. Our case further supports the role of SUPT5H as a potential β-globin chain production-modulating gene.

Objective: To assess the efficacy of positive feedback closed-loop management system (PFCMS) protocol in influencing parents' decision about pregnancy continuation in pregnancies diagnosed with omphalocele., Methods: This was a retrospective cohort study of patients who were diagnosed with fetal omphalocele prior to 20 weeks' gestation by ultrasound and were referred to Fetal Care Center at a mainland Chinese medical center during an 11-year period. Two management strategies were offered during the two stages of the study period: a single consultant with a routine protocol and a multidisciplinary support team with PFCMS, respectively. We analyzed the two protocols influencing parents' decision about pregnancy continuation., Results: Forty-nine patients diagnosed with fetal omphalocele were included in this study. In Group A including 16 patients with routine protocol during the first stage of the study period, the majority opted for termination, and only five continued the pregnancy. In Group B including 33 patients with PFCMS during the second stage of the study period, less than one third chose TOP, and 23 ended in live births. There was a significantly lower TOP rate in patients treated with the PFCMS protocol., Conclusion: The PFCMS protocol may be an efficient approach in managing pregnancies complicated by omphalocele, which may help in preventing unnecessary pregnancy terminations.

Objective: The aim of this prospective study is to evaluate the performance of the intermediate 16-week ultrasound in fetuses with increased nuchal translucency (NT) and a normal chromosomal microarray analysis (CMA)., Methods: During a one-year period, a detailed ultrasound was performed at 16 week' gestation for patients with an increased NT (≥3.5 mm) and normal CMA. Pregnancy work-up included a traditional 22-week ultrasound scan, an echocardiography, and the option of a 10-gene Rasopathy panel after a normal 16-week scan. Abnormal findings and pregnancy outcomes were collected and analyzed., Results: In 52 fetuses with an isolated increased NT and normal CMA, 14 (26.5%) were noted to have structural defects on the 16-week ultrasound. Intrauterine fetal death occurred in one (1.9%) case identified by the 16-week scan. Of the remaining 37 cases, six opted for a RASopathy panel. In this group, one case of Noonan syndrome was detected. One case of unilateral duplex kidney had not been found until the 22-week scan. One case of fetal growth restriction was identified in the third trimester. The remaining 34 cases proceeded with normal ultrasound to term., Conclusion: The 16-week ultrasound scan performed on fetuses with increased NT and normal CMA could detect the majority of structural abnormalities that are expected to be identified traditionally at 20-24 weeks.

Hb Zürich-Albisrieden, [α59(E8)Gly→Arg, HBA1 : c.178G>C] is a rare and highly unstable α-globin chain variant. The involved mutation has been reported in both HBA1 and HBA2 genes. A few compound heterozygotes of Hb Zürich-Albisrieden and α 0 -thalassemia have shown that this variant is associated with severe Hb H disease. We describe here another case of Hb Zürich-Albisrieden who presented with transfusion-dependent anemia beginning shortly after birth.

We describe a new β -globin mutation causing silent β -thalassemia ( β -thal). The proband was a 5-year-old boy who presented with the phenotype of thalassemia intermedia. Molecular diagnoses revealed a genomic alteration at position 1606 of the HBB gene ( HBB :c.*132C>G) in combination with a common β 0 -thal mutation ( HBB :c.126_129delCTTT). The 3'-untranslated region (UTR) mutation was inherited from his father who showed a normal mean corpuscular volume (MCV) and Hb A 2 level. The discovery of rare mutations provides important information related to both genetic counseling for families involved.

The aim of this study was to present prenatal ultrasound findings, molecular testing results and pregnancy outcomes of cases with 22q11.2 deletion (del22q11.2) diagnosed prenatally. A total of 76 foetuses were included. All cases were diagnosed by using chromosomal microarray analysis. Data on prenatal diagnosis, ultrasound findings, pregnancy outcomes and inheritance of del22q11.2 were reviewed. Congenital heart defects (CHDs) were the most common indications (47/76, 61.8%) for prenatal testing and were isolated in 52.6% (40/76). The constitution of CHDs comprised predominantly of conotruncal defects (61.7%; 29/47). Other cardiac anomalies were encountered in 38.3% (18/47) of cases. Extracardiac findings, including unilateral multicystic dysplastic kidney, clubfoot, increased nuchal translucency, intrauterine growth retardation and polyhydramnios, were found in 31.6% (24/76) of cases, and were combined with CHDs in 7 cases. Twelve cases had normal sonographic scans at the time of prenatal diagnosis. Foetal CHDs, especially conotruncal defects, are the most predictive association with del22q11.2. The information about del22q11.2 should also be part of the contents in comprehensive pre-test counselling even for those who are referred for diagnostic testing with foetal extracardiac findings.Impact statement What is already known on this subject? 22q11.2 deletion (del22q11.2) is the most common microdeletion syndrome in humans. At present, the main indications for prenatal testing for del22q11.2 are pregnancies of abnormal sonographic findings, especially foetal congenital heart defects. What do the results of this study add? Many extracardiac malformations, including some lethal or mildly non-specific ones, could be associated with foetal del22q11.2. There were also del22q11.2 foetuses had normal sonographic scans at the time of prenatal diagnosis. What are the implications of these findings for clinical practice and/or further research? The information about del22q11.2 should also be part of the contents in comprehensive pre-test counselling even for those who are referred for diagnostic testing with indications other than foetal cardiac anomalies.

We report a de novo frameshift mutation in exon 3 of the β-globin gene that leads to a β-thalassemia (β-thal) intermedia (β-TI) phenotype in a 6-year-old Chinese boy. This novel mutation with deletion of the last nucleotide (-T) at codon 130 results in a β-globin chain that is extended to 156 amino acid residues. This study highlights the importance of considering dominantly inherited β-thal in the investigation of anemia, even in patients with ethnic backgrounds not usually associated with β-thal and hematologically normal parents.

Introduction: Genetically, complete hydatidiform mole (CHM) is androgenetic diploid, containing two sets of paternal chromosomes. In most cases, recurrent HM (RHM) is CHM but has diploid biparental chromosome constitution. Case report: We report a mother with RHM, both with biparental diploidy. The mother was compound heterozygous for two variants, c.1720dup, p.(C574Lfs*4) and c.2165A > G, p.(D722G) of the NLRP7 gene, as was a brother who fathered 2 normal pregnancies. Conclusion: The genotype study should be obtained for patients of CHM, even in their first pregnancy, followed by genetic screening for maternal-effect variants in those with biparental moles. This strategy will identify patients in their first pregnancy with HM that have a decreased chance for a normal pregnancy, to allow genetic counseling, perhaps utilizing a donor egg.

Purpose: The aim of this study is to evaluate the impact of the utility of maternal cell-free DNA (cfDNA) on the number of chorionic villus sampling (CVS) at a mainland Chinese maternal hospital., Methods: This was a retrospective cohort study conducted in consecutive singleton pregnancies that underwent CVS between the 11th and 14th gestational weeks at a Chinese maternal hospital during a nine-year period. The indications, complications and prenatal diagnosis results were evaluated., Results: This study consisted of 5108 CVS procedures, including 2000 performed for fetal karyotyping, and 3108 performed for fetal single-gene genotyping. During the period with the introduction of cfDNA, the proportion of the number of CVS procedures for the indication of positive serum screening declined significantly, and abnormal ultrasound was the main indication for CVS performed for fetal karyotyping. Thalassemia was always the main indication for CVS, accounting for 50.5% of all CVS cases., Conclusions: cfDNA has changed the spectrum of CVS indications. CVS is now the invasive procedure performed for patients with a fetus having a very high risk of fetal genetic defects, including fetuses having major abnormal ultrasound or having a risk of single-gene disorder inherited from their parents.

We report a new hemoglobin (Hb) variant that we have named Hb Wanjiang ( HBB : c.255_264delinsTTTTTCTCAG). We identified this variant in a Chinese man by the next-generation sequencing (NGS) method. The father of the proband also carried the same variant. This variant results from a 10 bp deletion at codons 84-87 of the β-globin chain, replaced with 10 nucleotides coming from the δ-globin gene at the same position, leading to the substitution of two amino acids in the peptide chain with no change in the β-globin chain length. The heterozygotes had a normal hematological feature with no abnormal Hb variant detectable on capillary electrophoresis (CE) and high performance liquid chromatography (HPLC). The combination of Hb Wanjiang and β-thalassemia (β-thal) was not found to aggravate anemia.

The 3' untranslated region (3'UTR) is associated with mRNA stability because of its involvement in 3' end processing, polyadenylation, and mRNA capping. Mutations located in this area can cause a phenotype compatible with β + -thalassemia (β + -thal). We report a Chinese subject with β-thal intermedia (β-TI) who developed transfusion-dependent anemia. Molecular studies revealed that the patient was a compound heterozygote for two β-thal alleles: codons 41/42 (-TTCT) ( HBB : c.126_129delCTTT) and term codon +32 (A>C) ( HBB : c.*32A>C).

Objective: In this study, we report the indications for prenatal cytogenetic diagnosis of triploid cases, in an attempt to identify clues to early diagnosis., Study Design: This was a retrospective analysis of prenatal cases of triploidy during a 9-year period at mainland China. Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, fetal ultrasound findings, and pregnancy outcomes., Results: A total of 22 singleton pregnancies affected with triploid fetuses were detected. The fetal karyotype included 69,XXX (72.7%) and 69,XXY (27.3%). Eighteen cases were identified by the first trimester screening program. One case was missed by maternal cell-free DNA testing, but detected by second trimester anatomy scan. Three cases escaped the first trimester screening and were detected by second trimester anatomy scan., Conclusions: The present study demonstrates that most triploid cases can be diagnosed prenatally during the first trimester. The early asymmetrical fetal growth restriction, structural anomalies, and extremely high risk serum screening result for trisomy 21 or 18 should alert the physicians to the investigation of triploidy., Key Message: Ultrasound-based first-trimester screening plays a major role in early diagnosis of fetal triploidy. Future replacement of routine first-trimester screening by cell-DNA testing might miss the chance of early diagnosis and management of triploid pregnancies.

Homozygous or compound heterozygous mutations of the β-globin gene lead to β-thalassemia (β-thal) major (β-TM) or β-thal intermedia (β-TI), whereas heterozygotes usually show microcytosis with negligible or no hemolysis. Certain missense mutations in exon 3, however, produce unstable globins causing a dominant β-thal phenotype or hemolytic anemia in heterozygotes. Here we report a mutation in exon 3 of the β-globin gene, which results in an unstable globin (Hb Dieppe) [β127(H5)Gln→Arg; HBB : c.383A>G] with a dominant β-thal phenotype in two generations of a Chinese family. Physicians should be alerted to this mechanism of β-thal considering its relative rarity.

We have identified a new α chain hemoglobin (Hb) variant in a Chinese subject. Sequencing of the α-globin gene revealed a mutation in exon 1 at nucleotide 55, which results in the replacement of a glycine by cysteine at codon 18 [α18(A16)Gly→Cys, HBA2 : c.55G>T] that we have named Hb Jiujiang for the region of origin of the proband.

We describe a new δ/β fusion gene causing β-thalassemia (β-thal) trait and its formation mechanism. The proband was a 39-year-old woman who presented with persistent microcytic microcytosis without iron deficiency. Molecular diagnoses revealed a δβ configuration within a 54 bp region between the Cap site (+22) and codon 8, causing a deletion (NG_000007.3: g.63154_70565del). This results in a variant that has been named Hb Lepore-Hong Kong and shows a decreased β-globin mRNA in carriers compared to that of normal subjects. It is assumed that combination of this variant with β-thal may cause severe β-thal syndrome.

Objective: Only a small number of reports have been made on the prenatal ultrasound findings observed in 1p36 deletion syndrome. We explored prenatal diagnosis of 1p36 deletion by ultrasound as well as chromosomal microarray (CMA), and delineated the fetal presentation of this syndrome., Study Design: This was a retrospective analysis of 10 new prenatal cases of 1p36 deletion identified by CMA at a single Chinese medical center. Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, sonographic findings, CMA results and pregnancy outcomes., Results: One case was diagnosed because of a positive cell-free DNA (cfDNA) testing result for terminal 1p deletion, and the remaining nine cases were identified because of an abnormal ultrasound findings, including early miscarriage, structural abnormalities and fetal growth restriction. CMA revealed 1p36 deletions to be terminal in six cases, and interstitial in four cases. Deletion sizes ranged from 1.7 to 42.7 Mb., Conclusions: Prenatal findings such as cardiac malformations, especially Ebstein anomaly, and fetal growth retardation should warrant the diagnosis of 1p36 deletion and invasive genetic testing using CMA.

We report a rare mutation, HBA2 : c.184A>T on the α2-globin gene, detected in a Chinese proband who presented with Hb H disease and a mild anemia. This frameshift mutation results in a premature termination of translation at position 61 of the α2-globin gene. Carriers of this mutation showed a borderline microcytic hypochromia. Our study indicates the importance of screening nondeletional α-thalassemia (α-thal) in areas with a particularly high prevalence of thalassemia such as in Southern China, especially for couples with one partner carrying an α 0 -thal deletion.

We describe a new α-globin chain variant in a Chinese subject. This novel variant, with a Val→Met substitution at codon 93 of the α-globin chain, has been named Hb Qingcheng ( HBA1 : c.280G>A) for where the proband was born. A woman with somatic mosaicism for Hb Qingcheng presented with the phenotype of mild α-thalassemia (α-thal).

Objective: To evaluate whether cell-free DNA (cfDNA) testing could replace an invasive procedure in pregnancies with isolated fetal omphalocele. Study design: This was a retrospective study of all pregnancies with sonographically detected fetal omphalocele at three tertiary referral centers between 2012 and 2016. Invasive diagnostic testing was performed for genetic investigations using conventional karyotyping or chromosomal microarray. cfDNA testing was assumed to be offered to patients with isolated fetal omphalocele for screening for common aneuploidies. Results: Invasive genetic testing was performed in a total of 107 pregnancies with a fetal omphalocele. Abnormal karyotype was found in 66% (31/47) of nonisolated omphalocele cases and in 1.7% (1/60) of isolated omphalocele cases. No pathogenic copy number variations (CNVs) were detected in 59 cases with isolated omphalocele and normal karyotype. If cfDNA screening was used in cases with isolated omphalocele, the affected fetus with trisomy 18 would be detected, and no rare chromosomal aberrations or submicroscopic pathogenic CNVs would be missed. Conclusions: cfDNA testing could be recommended for prenatal genetic evaluation in pregnancies with isolated fetal omphalocele after thorough pretest counseling. Key Message: A very low percentage of aneuploidies and rare chromosomal/subchromosomal abnormalities are found in prenatal cases of isolated omphalocele. It seems that for pregnancies with isolated omphalocele, cfDNA testing represents an alternative for patients who choose to continue the pregnancies and are reluctant to undertake invasive diagnostic testing.

Anemia is common in patients with systemic lupus erythematosus (SLE). The association between thalassemia and SLE is rare. In this study, we report the first patient who was found to have a severe hemolytic anemia caused by combination of SLE and Hb H disease. The patient had a more severe presentation in the hematological system. Our case indicates that for a patient who was diagnosed with SLE and developed deterioration in her hematological cell lines, investigation of other possible coexisting causes would be warranted.

Objective: The aim of this study was to evaluate the utility of chromosomal microarray (CMA) in patients who were solely referred for molecular diagnosis. Methods: During a 2-year period, CMA was the patients' choice, whether to opt for it or not, for those at risk for fetal hemoglobin Bart's disease or β-thalassemia major who were referred for invasive prenatal diagnosis and had a normal fetal genotype. CytoScan 750 K array (Affymetrix Inc., Santa Clara, CA) was used for CMA. The CMA testing results were collected. Results: There were 184 patients, who had a normal genotypic result, opting CMA testing without an obvious indication for fetal karyotyping. The median maternal age was 29 years (range, 17-34); the median gestational age was 13 weeks (range, 11-20). In two out of 184 (1.1%) cases unexpected de novo pathogenic microdeletions were found: a 3.2 Mb 22q11.21 microdeletion and a 0.8 Mb 16p11.2 microdeletion. Conclusions: Pregnancies at risk for thalassemia can also benefit from performing CMA. This information might be a part of the contents in comprehensive pretest counseling for those who are referred for diagnostic testing due to a molecular disorder.

Genetic recombination between homologous sequences on the human globin gene clusters can lead to the creation of fusion genes. In this study, we report the detection of an α-globin fusion gene by using real-time polymerase chain reaction (qPCR)-based multicolor melting curve analysis (MMCA). The carriers of this fusion gene had a mild α-thalassemia phenotype with a normal hemoglobin (Hb) value and borderline hematological indices. Sequence analysis revealed that the mutant gene was the result of a fusion between the α2 and ψα1 genes. Our results indicate that the MMCA has the ability to detect the fusion gene, which is helpful for genetic counseling in thalassemia prevalent areas.

Thalassemia is a great health burden in mainland China. Carrier screening and prenatal diagnosis (PND) are essential for its prevention. The aim of this study was to describe the trend in the timing of PND for thalassemia in at-risk families in mainland China. All women who were at-risk for thalassemia and received PND at a mainland Chinese tertiary obstetric center between 2011 and 2019 were included. Information required for the survey was obtained from the database of the institute. In total, 4045 women underwent PND for thalassemia, including 1720 for β-thalassemia (β-thal) and 2325 for α-thalassemia (α-thal). The median gestational age for the PND procedure was 13 weeks. The number of PNDs performed increased year by year over this period. For both β-thal and α-thal, the proportion of women undergoing early PND also increased along with the time span. A total of 428 cases was diagnosed prenatally to be affected with β-thal major (β-TM) and 769 were affected with Hb Bart's disease. Most of the β-TM pregnancies and all of the Hb Bart's disease pregnancies were terminated. With the implementation of effective screening measures, births of affected infants have been dramatically avoided, and early PND has become the main approach, thus allowing the possibility of obtaining results at an earlier stage of pregnancy.

The -50 (G>A) ( HBB : c.-100G>A) mutation was first reported as a β-thalassemia (β-thal) allele in a Chinese family. However, the hematological features of carriers with this variant are not available. In this study, we present the hematological data associated with -50 (G>A) to determine its phenotype. During a 4-year period, eight simple heterozygotes and three double heterozygotes for the -50 mutation and α-thalassemia (α-thal) were included. The simple heterozygotes had normal hematological parameters. The double heterozygotes had the hematological findings of simple α-thal heterozygotes. Two subjects with a compound heterozygosity for -50 and β-thal were also found, and both had typical hematological parameters of β-thal trait. Therefore, we present evidence that -50 (G>A) is likely a silent β-thal allele. Compound heterozygotes for -50/β-thal had no phenotype of severe β-thal. This information might be helpful in genetic counseling for couples in thalassemia high-prevalence areas.

Objective: To report the experience with first-trimester prenatal detection of pregnancies complicated by trisomy 18. Study design: Proven cases of trisomy 18 identified between 11 and 14 weeks of gestation were retrospectively reviewed. Information on maternal demographics, prenatal sonographic findings, indications for prenatal diagnosis and chromosomal analysis results was obtained by reviewing medical records. Results: During the 7-year period from January 2011 to December 2017, 89 cases of full trisomy 18 had first-trimester indications for prenatal diagnosis at Guangzhou Women and Children's Medical Center. Eighty-five (95.5%) had abnormal sonographic findings in the first trimester. The most common finding was increased nuchal translucency (55.1%), followed by cystic hygroma (18.0%), omphalocele (14.6%), and fetalis hydrops (11.2%). Four cases (4.5%) were not associated with any abnormal first-trimester sonographic finding, and were diagnosed because of routine positive screening results for trisomy 18. A single case was diagnosed because of a positive cell-free DNA (cfDNA) result. Conclusion: These results demonstrate that a large number of fetuses with trisomy 18 have abnormal sonographic findings in the first trimester, and support the continued utility of first-trimester sonographic examination in the diagnosis of this trisomy even with the availability of cfDNA.

Hb Westmead (α122(H5)His>Gln) ( HBA2 : c.369C>G) is a common α-globin variant causing α-thalassemia (α-thal) in Mainland China. In this study, we report the hematological characteristics in Hb Westmead carriers in a Chinese population. There were 546 individuals carrying Hb Westmead based on their molecular diagnosis: 514 Hb Westmead heterozygotes and 32 compound heterozygotes for Hb Westmead and α 0 -thal. Compared to common deletional α + -thal, Hb Westmead was associated with higher mean corpuscular hemoglobin (Hb) (MCH) values. Compound heterozygotes for Hb Westmead and α 0 -thal showed significantly higher Hb, mean corpuscular volume (MCV) and MCH values than subjects with deletional Hb H disease. When compared to α 0 -thal carriers, compound heterozygotes for Hb Westmead and α 0 -thal showed similar Hb values, but significantly lower MCV and MCH values. Our results indicate that Hb Westmead is a silent nondeletional α + -thal, with a deficiency of α-globin chain milder than deletional α + -thal, and compound heterozygotes for Hb Westmead/α 0 -thal have a phenotype similar to simple α 0 -thal.

Hb Constant Spring (Hb CS) ( HBA2 : c.427T>C) is a common α-globin variant causing α-thalassemia (α-thal) phenotypes in mainland China. In this study, we evaluated the efficiency of erythrocyte parameters and capillary electrophoresis (CE) in the determination of Hb CS in blood samples from Hb CS carriers. Based on molecular diagnosis, there were 462 patients carrying Hb CS: 411 Hb CS heterozygotes, seven carried Hb H-Hb CS disease, 18 compound heterozygotes for Hb CS/α + -thal, and 26 double heterozygotes for Hb CS and β-thalassemia (β-thal). Forty-three cases had no Hb CS peak visible on CE, including all 26 cases of double heterozygotes for Hb CS and β-thal, and 17 cases of heterozygotes carrying only Hb CS. Hb CS heterozygotes, those without a Hb CS peak, presented with lower hemoglobin (Hb), mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) values than those with a Hb CS peak. The MCV <80.0 fL yielded a detection rate of 87.8% for screening individuals carrying Hb CS. Therefore, we emphasize that if one partner of a couple has tested positive for α 0 -thal, the other should be subjected to detailed screening for this nondeletional allele using molecular analysis, regardless of his/her red cell indices and electrophoretic chromatogram.

Introduction: Congenital diaphragmatic eventration (CDE) is defined as the abnormal elevation of the diaphragm, due to incomplete muscularization of the diaphragm with a thin membranous sheet replacing normal diaphragmatic muscle. Case report: We report a prenatal case with a diaphragmatic mesothelial cyst combined with CDE. Conclusion: A large cystic mass between the thoracic wall and the liver in early pregnancy is highly suggestive of cystic diaphragm.

A female of Chinese origin carried the codon 43 (G>T) ( HBB : c.130G > T) and codons 71/72 (+A) ( HBB : c.216&#95;217insA) mutations of the β-globin gene in cis , identified during prenatal thalassemia screening. The double in cis mutations were inherited from her mother. Both of the two carriers behave as a traditional heterozygote for β-thalassemia (β-thal) with microcytosis and a high Hb A 2 level. This case report indicates that the possibility of multiple mutations in cis in a fetus with thalassemia trait has to be considered in a prenatal screening program.

In this study, we report on a compound heterozygote for variants in the key erythroid transcription factor Krüppel-like factor 1 ( KLF1 ) gene in a patient who presented with severe, transfusion-dependent hemolytic anemia. The red cells were normochromic and normocytic, and resembled those seen in patients with congenital nonspherocytic hemolytic anemia (CNSHA). Next generation sequencing (NGS) revealed that the patient was a compound heterozygote for the KLF1 frameshift variant c.519&#95;525dup (p.Gly176ArgfsTer179) and a missense variant c.1012C>A (p.Pro338Thr). This report adds to the wide clinical spectrum of KLF1 gene variants. We suggest that loss of KLF1 should be considered in otherwise unexplained cases of congenital hemolytic anemia.

The 17q12 deletion syndrome is a chromosomal anomaly resulting from the interstitial microdeletion of the long arm of chromosome 17. The aim of this study was to present the experience on prenatal diagnosis of 17q12 deletion to further define the prenatal phenotypes of this syndrome. Eleven pregnancies with foetal 17q12 deletion detected by chromosomal microarray (CMA) were retrospectively included at a single Chinese tertiary medical centre. Clinical data were reviewed for these cases, including the maternal demographics, foetal ultrasound findings, CMA results and pregnancy outcomes. The deletion sizes of 17q12 ranged from 1.42 to 1.94 Mb. The deletion had arisen de novo in 10 cases and inherited from one of the parents in one case. Variable kidney abnormalities were found by ultrasound in all of the cases, with bilateral or unilateral hyperechogenic kidneys being the most common findings. This study indicates that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and prenatal testing with CMA should be offered to the foetal cases of hyperechogenic kidneys. Impact statement What is already known on this subject? 17q12 deletion syndrome is a cause of renal abnormalities, maturity-onset diabetes of the young and neurodevelopmental disorders. Prenatal diagnosis has been reported in several isolated cases with the use of microarray-based technologic means. What do the results of this study add? The results provide further evidence that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and genetic testing should be offered to foetal cases with hyperechogenic kidneys. A rare prenatal case of 17q12 deletion with multiple structural malformations and anhydramnios is presented. What are the implications of these findings for clinical practice and/or further research? There should be a high index of suspicion of carriers in parents when 17q12 deletion is confirmed prenatally. An extremely wide phenotype spectrum of this deletion should be emphasised in the prenatal counselling.

More than 900 abnormal hemoglobin (Hb) β chain variants have now been characterized. The majority are due to point mutations resulting in a single amino acid substitution within the globin gene involved, with nearly twice as many β chain variants identified compared to α chain variants. Although most of these variants are clinically and hematologically silent, they can interact with different thalassemia mutations, which could sometimes render laboratory diagnostics in a routine setting difficult. In this study, we present a case of coinheritance of Hb City of Hope [β69(E13)Gly→Ser; HBB : c.208G>A] and β-thalassemia (β-thal), that compromises the molecular diagnosis of β-thal trait.

Patients with the β 0 /β 0 type of β-thalassemia (β-thal) usually present as β-thal major (β-TM), and are transfusion-dependent. However, the clinical and hematological features of β-thal can be modulated by different modifiers, resulting in a wide range of clinical severity even in patients with the same genotypes. We report a Chinese family with twin brothers, both of whom had the same genotype of β 0 /β 0 . One twin was diagnosed as β-TM at 4 months of age and had regularly been transfused; conversely the other twin with a KLF1 ( Krüppel-like factor 1 ) gene mutation, behaved as β-thal intermedia (β-TI), and had never been transfused. Our findings indicate that KLF1 mutations have a role in modulating the phenotypic severity of β-thal. The exact investigation of KLF1 modifiers is necessary in areas where globin gene disorders are most prevalent. This will be helpful in genetic counseling and optimizing the guidelines for prenatal diagnosis (PND) programs.

A regulatory single nucleotide polymorphism (rSNP), the A γ (+25 G>A) (rs368698783) (NG&#95;000007.3: g47783G>A) located in the HBG1 proximal promoter, is a significant predictor of clinical severity by elevating Hb F levels in β-thalassemia (β-thal). In this study, the presence of the A γ (+25 G>A) and A γ (+25 A>A) genotypes was investigated in four subgroups from a total of 611 subjects, including 88 α-thalassemia (α-thal) carriers (group A), 162 β-thal carriers of point mutations (group B), 57 carriers of β-thal deletions (group C) and 152 non thalassemic individuals (group D). The result is that the genotypes G>A and A>A exhibit significantly high levels of Hb F compared with the genotype G>G in both groups B and C, while no significant difference was observed in both groups A and D. We assume that the effect of A γ (+25 G>A) polymorphism on Hb F production is only under erythropoietic stress characteristic for β-globin chain deficiency.