Why NIPT should be publicly funded

Asking pregnant women to (co)pay for non-invasive prenatal testing (NIPT) out of pocket leads to unequal access across socioeconomic strata. To avoid these social justice issues, first-trimester prenatal screening should be publicly funded in countries such as the Netherlands, with universal coverage healthcare systems that offer all other antenatal care

Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes

Backgroun: The of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause triphalangeal thumb (TPT) and polydactyly in affected families. Objective: In thisreport, we describe two families with mild phenotypical presentation Methods: Weperformed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing. Results: In familyI, a novel 165A>G variant in the ZRS(g.156584405A>G, GRCh37/Hg19) was found. Infamily II, we identified a 295T>C variant inthe ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who werepresumed to be unaffected shared the variant in the ZRS with affected familymembers, suggesting reduced penetrance of the genotype. However, clinicalexamination of these unaffected family members revealed minor anomalies likebroad thumbs and lack of thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that theseZRS variants are minimally disruptive for Sonic Hedgehog expression andtherefore can result in subclinical phenotypes. Conclusion: Our study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT

Should pregnant women be charged for non-invasive prenatal screening? Implications for reproductive autonomy and equal access

The introduction of non-invasive prenatal testing (NIPT) in healthcare systems around the world offers an opportunity to reconsider funding policies for prenatal screening. In some countries with universal access healthcare systems, pregnant women and their partners are asked to (co)pay for NIPT. In this paper, we discuss two important rationales for charging women for NIPT: (1) to

Variant type and position predict two distinct limb phenotypes in patients with GLI3-mediated polydactyly syndromes

Introduction: Pathogenic DNA variants in the GLI-Kruppel family member 3 (GLI3) gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-Type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported GLI3 variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant. Methods: Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes. Results: 297 cases were identified with 127 different variants in the GLI3 gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013 and Beta: 2.548, p<0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p<0.001). Conclusion: There are two distinct phenotypes within the GLI3-mediated polydactyly population: Anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies

Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: Report of five infants

Five infants (two girls and three boys) from four families all had severe pre- and post-natal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%-83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%-41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2-16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483-486]), was discussed in connection with tumor development and progression

The Psychological Impact of Prenatal Diagnosis and Disclosure of Susceptibility Loci: First Impressions of Parents’ Experiences

Genomic microarray may detect susceptibility loci (SL) for neurodevelopmental disorders such as autism and epilepsy, with a yet unquantifiable risk for the fetus. The prenatal disclosure of susceptibility loci is a topic of much debate. Many health care professionals fear that reporting susceptibility loci may put a psychological burden on pregnant couples. It is our policy to disclose prenatal susceptibility loci as we recognize them as actionable for prospective parents. The aim of this report was to evaluate the psychological impact of disclosing a prenatal diagnosis of susceptibility loci. The psychological impact of disclosing susceptibility loci was evaluated in the first patients who received such results. Eight out of 15 women who had a susceptibility locus disclosed and four of their partners consented to share their experiences through a telephonic evaluation (n = 12). Follow-up time ranged from 3 to 15 months after their prenatal test result. The reporting of susceptibility loci was initially ‘shocking’ for five parents while the other seven felt ‘worried’. Ten out of 12 participants indicated they would like to be informed about the susceptibility locus again, two were unsure. Most had no enduring worries. Participants unanimously indicated that pregnant couples should have an individualized pre-test choice about susceptibility loci (non)disclosure. We observed no negative psychological impact with the prenatal diagnosis and disclosure of SL on participants. A key factor in mitigating parental anxiety with SL disclosure appears to be post-test genetic counseling. Our report confirms that pregnant women and their partners prefer an individualized choice regarding the scope of prenatal testing

False negative NIPT results: Risk figures for chromosomes 13,18 and 21 based on chorionic villi results in 5967 cases and literature review

Non-invasive prenatal testing (NIPT) demonstrated a small chance for a false negative result. Since the "fetal" DNA in maternal blood originates from the cytotrophoblast of chorionic villi (CV), some false negative results will have a biological origin. Based on our experience with cytogenetic studies of CV, we tried to estimate this risk. 5967 CV samples of pregnancies at high risk for common aneuplodies were cytogenetically investigated in our centre between January 2000 and December 2011. All cases of fetal trisomy 13,18 and 21 were retrospectively studied for the presence of a normal karyotype or mosaicism < 30% in short-term cultured (STC-) villi. 404 cases of trisomies 13,18 and 21 were found amongst 5967 samples (6,8%). Of these 404 cases, 14 (3,7%) had a normal or low mosaic karyotype in STC-villi and therefore would potentially be missed with NIPT. It involved 2% (5/242) of all trisomy 21 cases and 7.3% (9/123) of all trisomy 18 cases. In 1:426 (14/5967) NIPT samples of patients at high risk for common aneuploidies, a trisomy 18 or 21 will potentially be missed due to the biological phenomenon of absence of the chromosome aberration in the cytotrophoblast

Stable X chromosome reactivation in female human induced pluripotent stem cells

In placental mammals, balanced expression of X-linked genes is accomplished by X chromosome inactivation (XCI) in female cells. In humans, random XCI is initiated early during embryonic development. To investigate whether reprogramming of female human fibroblasts into induced pluripotent stem cells (iPSCs) leads to reactivation of the inactive X chromosome (Xi), we have generated iPSC lines from fibroblasts heterozygous for large X-chromosomal deletions. These fibroblasts show completely skewed XCI of the mutated X chromosome, enabling monitoring of X chromosome reactivation (XCR) and XCI using allele-specific single-cell expression analysis. This approach revealed that XCR is robust under standard culture conditions, but does not prevent reinitiation of XCI, resulting in a mixed population of cells with either two active X chromosomes (Xas) or one Xa and one Xi. This mixed population of XaXa and XaXi cells is stabilized in naive human stem cell medium, allowing expansion of clones with two Xas

Congenital diaphragmatic hernia and chromosome 15q26: determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization

Congenital diaphragmatic hernia (CDH) has an incidence of 1 in 3,000 births and a high mortality rate (33%-58%). Multifactorial inheritance, teratogenic agents, and genetic abnormalities have all been suggested as possible etiologic factors. To define candidate regions for CDH, we analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. This study focused on the most frequent structural anomaly found: a deletion on chromosome 15q. We analyzed material from three of our patients and from four previously published patients with CDH and a 15q deletion. By using array-based comparative genomic hybridization and fluorescent in situ hybridization to determine the boundaries of the deletions and by including data from two individuals with terminal 15q deletions but without CDH, we were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, one patient with CDH harbored a small interstitial deletion. Together, these findings allowed us to define a minimal deletion region of approximately 5 Mb at chromosome 15q26.1-26.2. The region contains four known genes, of which two--NR2F2 and CHD2--are particularly intriguing gene candidates for CDH