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Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation. The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered. Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%. Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.

Purpose Variants in IQSEC2 , escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. Methods We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. Results IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. Conclusion This study provides a comprehensive overview of IQSEC2- related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Abstract Context The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. Results We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity. Conclusions Our patient’s phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient’s endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype. Homozygous truncating RAX mutations in a child, not only cause anophthalmia, but also hypopituitarism, diabetes insipidus, and cleft lip and palate, similar to the Rax knock-out mouse endocrine phenotype.

We present a case of a transient acquired zinc deficiency in a breast-fed, 4-month-old-male prematurely born infant, with acrodermatitis enteropathica-like symptoms such as crusted, eroded, erythemato-squamous eruption in periorificial and acral patterns. The laboratory investigations showed low zinc levels in the infant’s and the mother’s serum and in the mother’s milk; genetic analysis did not show any mutation in the SLC39A4 gene, involved in acrodermatitis enteropathica. Acquired zinc deficiency is often found in premature infants because of their increased requirement, the low serum and milk zinc levels in breastfeeding women being also an important risk factor, as in this case. A prompt zinc supplementation is essential for the good prognosis of the disease.

Wolf Reik and Ian Dunham and colleagues cloned and sequenced the complete IGF2-H19 locus in tammar wallaby, a marsupial. Functional analyses revealed conservation of imprinting mechanisms, including germline DNA methylation, between marsupials and eutherians. Comparisons between eutherians and marsupials suggest limited conservation of the molecular mechanisms that control genomic imprinting in mammals. We have studied the evolution of the imprinted IGF2-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs show miR-675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF insulator, and spreads somatically into the H19 gene. The conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution.

Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these \"common cold\" viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage immunoprecipitation sequencing. Seroprevalence of antibodies against endemic HCoVs ranged between approximately 4% and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid, and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2' cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and nonhuman coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.

The overproduction of endogenous chorionic gonadotropin during pregnancy has been associated with spontaneous ovarian hyperstimulation syndrome. Yet the syndrome has been observed in women with normal levels of chorionic gonadotropin. This Brief Report defines a mutation in the follicle-stimulating hormone (FSH) receptor that is associated with recurrent, spontaneous ovarian hyperstimulation syndrome. In this instance, the mutant receptor responded both to chorionic gonadotropin and to thyrotropin. The ovarian hyperstimulation syndrome most often occurs as an iatrogenic complication of ovarian-stimulation treatments for in vitro fertilization (the incidence of severe forms ranges from 0.5 to 5 percent). 1 The clinical manifestations vary from abdominal distention and discomfort to potentially life-threatening, massive ovarian enlargement and capillary leak with fluid sequestration in a third space. 2 Although the presence of human chorionic gonadotropin is invariably associated with the condition, the pathophysiological mechanism remains undefined. 3 The overproduction of endogenous chorionic gonadotropin during pregnancy has been associated with spontaneous ovarian hyperstimulation syndrome (also termed hyperreactio luteinalis of the first trimester), as well as with . . .

Background: Ciliopathies are rare diseases causing renal and extrarenal manifestations. Here, we report the case of a ciliopathy induced by a homozygous pathogenic variant in the TTC21B gene. Case Description: A 47-year-old patient started hemodialysis for chronic kidney disease (CKD) of unknown origin. She presented with early onset of hypertension, pre-eclampsia, myopia and cirrhosis. Renal biopsy showed mild interstitial fibrosis, tubular atrophy, and moderate arteriosclerosis while liver pathology demonstrates grade B biliary cirrhosis. Family history revealed several cases of early-onset severe hypertension and one case of end-stage renal disease (ESRD) needing kidney transplantation at twenty years of age. Clinical exome sequencing showed homozygosis for the pathogenic variant c.626C>T (p.Pro209Leu) in the TTC21B gene. The patient underwent combined liver-renal transplantation with an excellent renal and hepatic graft outcome. Conclusions: TTC21B gene mutations can lead heterogeneous to clinical manifestations and represent an underappreciated cause of ESRD. The paradigm in diagnosis of CKD of early onset and/or of unknown origin is changing and genetic counseling should be performed in all patients and families that meet those criteria. Renal or combined liver-renal transplantation represents the best option for patients suffering from those diseases in terms of prognosis and quality of life.

Very rare cases of pulmonary arterial hypertension (PAH) have been linked to homozygous or compound heterozygous von Hippel–Lindau (VHL) tumor suppressor gene mutations, while heterozygous VHL mutations lead to VHL tumor syndrome. Although those entities are defined, the genotype–phenotype correlation is incompletely understood, and patient management recommendations are lacking. Here, we describe a case of severe early‐onset PAH due to a so‐far unreported compound heterozygous association of VHL mutations and review the existing data.

After becoming competent for resuming meiosis, fully developed mammalian oocytes are maintained arrested in prophase I until ovulation is triggered by the luteotropin surge. Meiotic pause has been shown to depend critically on maintenance of cAMP level in the oocyte and was recently attributed to the constitutive Gs (the heterotrimeric GTP-binding protein that activates adenylyl cyclase) signaling activity of the G protein-coupled receptor GPR3. Here we show that mice deficient for Gpr3 are unexpectedly fertile but display progressive reduction in litter size despite stable age-independent alteration of meiotic pause. Detailed analysis of the phenotype confirms premature resumption of meiosis, in vivo, in about one-third of antral follicles from Gpr3-/-females, independently of their age. In contrast, in aging mice, absence of GPR3 leads to severe reduction of fertility, which manifests by production of an increasing number of nondeveloping early embryos upon spontaneous ovulation and massive amounts of fragmented oocytes after superovulation. Severe worsening of the phenotype in older animals points to an additional role of GPR3 related to protection (or rescue) of oocytes from aging. Gpr3-defective mice may constitute a relevant model of premature ovarian failure due to early oocyte aging.