Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005-2009: a prospective population-based cohort study

Background

Spinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25–50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program.

Methods and Findings

This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968.

Conclusion

The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling.     

An interstitial deletion of 8q23.3–q24.22 associated with Langer–Giedion syndrome,Cornelia de Lange syndrome and epilepsy

We present a 19-year-old male with laxity of skin and joints, sparse scalp hair, facial dysmorphism, epilepsy, multiple exostoses, scoliosis, gastroesophageal reflux, cardiovascular defects, and an 8q23.3–q24.22 deletion detected by array comparative genomic hybridization. The patient was previously misdiagnosed as having Ehlers–Danlos syndrome. However, his clinical findings are in fact correlated with trichorhinophalangeal syndrome type II/Langer–Giedion syndrome and Cornelia de Lange syndrome-4. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of TRPS1, RAD21, EXT1 and KCNQ3 in this case.     

Prenatal diagnosis of de novo interstitial deletions involving 5q23.1–q23.3 and 18q12.1–q12.3 by array CGH using uncultured amniocytes in a pregnancy with fetal interrupted aortic arch and atrial septal defect

We present prenatal diagnosis of de novo interstitial deletions involving 5q23.1–q23.3 and 18q12.1–q12.3 by aCGH using uncultured amniocytes in pregnancy with interrupted aortic arch and atrial septal defect in a fetus. The fetus postnatally manifested facial dysmorphisms and long slender fingers. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of FBN2, DTNA and CELF4 in this case.     

Chromosome 17p13.3 deletion syndrome: aCGH characterization,prenatal findings and diagnosis,and literature review

We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR) in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery. aCGH analysis revealed a 3.17-Mb deletion at 17p13.3, or arr [hg19] 17p13.3 (0–3,165,530)×1. The qPCR assays revealed a maternal origin of the deletion. Metaphase FISH analysis detected the absence of the LIS1 probe signal on the aberrant chromosome 17. The karyotype was 46,XX,del(17)(p13.3). We review the literature of chromosome 17p13.3 deletion syndrome with prenatal findings and diagnosis, and suggest that prenatal ultrasound detection of central nervous system anomalies such as lissencephaly, corpus callosum dysgenesis/agenesis, ventriculomegaly and microcephaly associated with IUGR, polyhydramnios, congenital heart defects, abdominal wall defects and renal abnormalities should include a differential diagnosis of chromosome 17p13.3 deletion syndrome.     

Cri-du-chat (5p-) syndrome presenting with cerebellar hypoplasia and hypospadias: Prenatal diagnosis and aCGH characterization using uncultured amniocytes

We present prenatal diagnosis of a de novo distal deletion involving 5p(5p15.1 → pter) using uncultured amniocytes in a pregnancy with cerebellar hypoplasia, hypospadias and facial dysmorphisms in the fetus. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of CTNND2, SEMA5A, TERT, SRD5A1 and TPPP. We speculate that haploinsufficiency of SRD5A1 and TPPP may be responsible for hypospadias and cerebellar hypoplasia, respectively, in this case.     

Prenatal diagnosis of partial trisomy 3q (3q27.3→qter) and partial monosomy 14q (14q31.3→qter) of paternal origin associated with fetal hypotonia,arthrogryposis, scoliosis and hyperextensible joints

We present rapid aneuploidy diagnosis of partial trisomy 3q (3q27.3→qter) and partial monosomy 14q (14q31.3→qter) of paternal origin by aCGH using uncultured amniocytes in a fetus with hypotonia, scoliosis, arthrogryposis, hyperextensible joints, facial dysmorphism, ventricular septal defect, pulmonary stenosis, clenched hands, clubfoot, scalp edema and right hydronephrosis. We discuss the genotype–phenotype correlation of 3q duplication syndrome and terminal 14q deletion syndrome. We demonstrate that fetuses with a paternal-origin deletion of 14q involving the 14q32.2 imprinted region may prenatally present the upd(14)mat-like phenotype such as hypotonia, scoliosis, arthrogryposis and hyperextensible joints.     

Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors

A series of isatin-β-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-β-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their antiherpetic activity. The synthesis and structure-activity relationship studies are presented.     

Accelerated clearance of polyethylene glycol-modified proteins by anti-polyethylene glycol IgM.

Tumor therapy by the preferential activation of a prodrug at tumor cells targeted with an antibody-enzyme conjugate may allow improved treatment efficacy with reduced side effects. We examined antibody-mediated clearance of poly(ethylene glycol)-modified beta-glucuronidase (betaG-sPEG) as a method to reduce serum concentrations of enzyme and minimize systemic prodrug activation. Enzyme-linked immunosorbent assay and immunoblot analysis of two monoclonal antibodies generated by immunization of BALB/c mice with an antibody-betaG-sPEG conjugate showed that mAb 1E8 (IgG1) bound betaG and betaG-sPEG whereas mAb AGP3 (IgM) bound poly(ethylene glycol). Neither antibody affected the betaG activity. mAb 1E8 and AGP3 were modified with 36 and 208 galactose residues (1E8-36G and AGP3-208G) with retention of 72 and 48% antigen-binding activity, respectively, to target immune complexes to the asialoglycoprotein receptor on liver cells. mAb 1E8 and AGP3 cleared betaG-PEG from the circulation of mice as effectively as 1E8-36G and AGP3-208G, respectively. mAb AGP3, however, cleared betaG-sPEG more completely and rapidly than 1E8, reducing the serum concentration of betaG-sPEG by 38-fold in 8 h. AGP3 also reduced the concentration of an antibody-betaG-sPEG conjugate in blood by 280-fold in 2 h and 940-fold in 24 h. AGP3-mediated clearance did not produce obvious damage to liver, spleen, or kidney tissues. In addition, AGP3 clearance of betaG-sPEG before administration of BHAMG, a glucuronide prodrug of p-hydroxyaniline mustard, prevented toxicity associated with systemic activation of the prodrug based on mouse weight and blood cell numbers. AGP3 should be generally useful for accelerating the clearance of PEG-modified proteins as well as for improving the tumor/blood ratios of antibody-betaG-PEG conjugates for glucuronide prodrug therapy of cancer.