Prenatal diagnosis of paternal uniparental disomy for chromosome 2 in two fetuses with intrauterine growth restriction

Abstract Uniparental disomy (UPD) is when all or part of the homologous chromosomes are inherited from only one of the two parents. Currently, UPD has been reported to occur for almost all chromosomes. In this study, we report two cases of UPD for chromosome 2 (UPD2) encountered during prenatal diagnosis. The ultrasound findings of the fetuses from two unrelated families showed intrauterine growth restriction. The karyotype analyses were normal. The two fetuses both had complete paternal chromosome 2 uniparental disomy detected by whole-exome sequencing, but their clinical outcomes were significantly different, with fetal arrest in case 1 and birth in case 2. In this report, we analyzed and discussed the phenotypes of the fetuses in these two cases and reviewed the literature on UPD2

Hb H disease associated with compound heterozygosity for --SEA deletion and a novel alpha globin chain variant (HBA2:c.175C>A) on the distal histidine in a Chinese family

ABSTRACTObjectives: In clinical practice, the majority of α-thalassaemia cases arise from deletions of the α-globin genes. However, a subset of cases is attributed to rare haemoglobin variants, which can manifest with borderline or normal screening results, potentially leading to missed diagnoses in clinical practice.Methods: Blood samples were collected from family members and underwent haematological, DNA and RNA analysis.Results: The five-month-old proband presented a haematological phenotype consistent with Hb H disease. The mother’s haematology profile was consistent with an α-thalassaemia carrier, while the father exhibited a borderline reduction in MCV and MCH. MALDI-TOF identified an abnormal α-chain in the proband. DNA analysis revealed a novel α-globin variant (HBA2:c.175C>A, α58His>Asn, Hb DG-Nancheng) affecting the distal histidine in the family. The father and the mother had α-genotype of --SEA/αα and αDG-Nanchengα/αα, respectively; while the proband inherited both mutant alleles (--SEA/αDG-Nanchengα). Sequencing of cDNA from HBA2 gene identified an equal ratio of normal and mutant alleles.Conclusion: This rare case highlighted the importance of identifying rare haemoglobin variant during prenatal screening. The clinical and genetic data provides useful information on the pathogenicity of this variant and further insight into the role of distal histidine residue of α-globin

A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

<jats:p><jats:italic>PACS1</jats:italic> neurodevelopmental disorder (<jats:italic>PACS1</jats:italic>-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of <jats:italic>PACS1</jats:italic>-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in <jats:italic>PACS1</jats:italic> that had been identified as pathogenic variants for <jats:italic>PACS1</jats:italic>-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in <jats:italic>PACS1</jats:italic> will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in <jats:italic>PACS1</jats:italic> (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of <jats:italic>PACS1</jats:italic>-NDD and demonstrates that the loss of function variation in <jats:italic>PACS1</jats:italic> displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.</jats:p&gt

Interface character distributions in WC/Co cemented carbide

Electron backscatter diffraction， five parameter analysis， overlap-pole-figure analysis and near coincident site analysis were used to investigate the interface character distributions of WC/WC grain boundaries and WC/Co phase boundaries in WC/Co cemented carbides under different heat treatment states. The results show that the WC/WC Σ2 grain boundaries with a fraction of 4.5% are generated in the oil-quenched sample after high temperature sintering. The fraction of Σ2 boundaries with interface matching features of ｛101¯0｝/｛101¯0｝ is 2.6%.The cobalt in this sample is basically face-centered-cubic structure， and the interface with the interface inter-connection features of ｛101¯0｝WC/｛001｝Co，｛101¯0｝WC/｛110｝Co and ｛112¯0｝WC/｛110｝Co is the main part of the WC/Co phase boundary. After tempering at 800 ℃， the samples with atmosphere protection and slow cooling in the furnace have the proportion and characteristics of WC/WC Σ2 grain boundaries， which are very close to those of oil-quenched samples.The cobalt in this sample is primarily hexagonal structure， and the interface with the interface inter-connection features of ｛101¯0｝WC/｛101¯0｝Co and ｛112¯0｝WC/｛112¯0｝Co is the main part of the WC/Co phase boundary

Tandem Mass Spectrometry Screening for Inborn Errors of Metabolism in Newborns and High-Risk Infants in Southern China: Disease Spectrum and Genetic Characteristics in a Chinese Population

<jats:p>Inborn errors of metabolism (IEMs) often causing progressive and irreversible neurological damage, physical and intellectual development lag or even death, and serious harm to the family and society. The screening of neonatal IEMs by tandem mass spectrometry (MS/MS) is an effective method for early diagnosis and presymptomatic treatment to prevent severe permanent sequelae and death. A total of 111,986 healthy newborns and 7,461 hospitalized high-risk infants were screened for IEMs using MS/MS to understand the characteristics of IEMs and related gene mutations in newborns and high-risk infants in Liuzhou. Positive samples were analyzed by Sanger sequencing or next-generation sequencing. The results showed that the incidence of IEMs in newborns in the Liuzhou area was 1/3,733, and the incidence of IEMs in high-risk infants was 1/393. Primary carnitine deficiency (1/9,332), phenylketonuria (1/18,664), and isovaleric acidemia (1/37,329) ranked the highest in neonates, while citrullinemia type II ranked the highest in high-risk infants (1/1,865). Further, 56 mutations of 17 IEMs-related genes were found in 49 diagnosed children. Among these, <jats:italic>HPD</jats:italic> c.941T > C, <jats:italic>CBS</jats:italic> c.1465C > T, <jats:italic>ACADS</jats:italic> c.337G > A, c.1195C > T, <jats:italic>ETFA</jats:italic> c.737G > T, <jats:italic>MMACHC</jats:italic> 1076bp deletion, <jats:italic>PCCB</jats:italic> c.132-134delGACinsAT, <jats:italic>IVD</jats:italic> c.548C > T, c.757A > G, <jats:italic>GCDH</jats:italic> c.1060G > T, and <jats:italic>HMGCL</jats:italic> c.501C > G were all unreported variants. Some related hotspot mutations were found, including <jats:italic>SLC22A5</jats:italic> c.51C > G, <jats:italic>PAH</jats:italic> c.1223G > A, <jats:italic>IVD</jats:italic> c.1208A > G, <jats:italic>ACADS</jats:italic> c.625G > A, and <jats:italic>GCDH</jats:italic> c.532G > A. These results show that the overall incidence of IEMs in the Liuzhou area is high. Hence, the scope of IEMs screening and publicity and education should be expanded for a clear diagnosis in the early stage of the disease.</jats:p&gt

Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies