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Congenital structural heart disease (CHD) is the leading cause of infant death from birth defects. Postnatal survival primarily depends on the type and severity of the defect. In addition, worse cardiac prognosis is observed when extra-cardiac anomalies (ECA) are associated. This retrospective chart review was aimed at finding markers for short-term outcome prediction of prenatally-diagnosed complex CHD, focusing in particular on the impact of CHD category, of CHD severity score and of prenatal or postnatal diagnosis of ECA or chromosomal anomalies on 4 primary outcomes: termination of pregnancy (TOP), intrauterine fetal demise, neonatal mortality and 1-year-survival rate. We reviewed medical files from 381 fetuses, presenting at our center between 2018 and 2021 with CHD for which prenatal advice by a pediatric cardiologist was sought. 341 fetuses met the inclusion criteria for the study. Twin pregnancies (7.62%; OR 4.76 ( p  < 0.001)) and pregnancies resulting from assisted reproductive technology (7.33%; OR 2.44 ( p  < 0.001)) were more prevalent compared to the general population. CHD categories and CHD severity scores, ranging from A (extremely high risk based on CHD or ECA type) to D (low risk), were assigned to each fetus. Prenatal or postnatal chromosomal microarray results were available for 232 fetuses (68%) and were abnormal in 30 (12.9%). Logistic regression analysis was used to determine significant predictors for the primary outcomes ‘TOP’, ‘postnatal demise before the age of 1 month’ and ‘survival at the age of 1 year’. TOP was carried out significantly more with: prenatal genetic diagnosis, severity score A and severity score B. Interestingly, a prenatal genetic diagnosis was negatively correlated with pregnancy continuation, but it was not a significant predictor for postnatal mortality, while a postnatal diagnosis of a genetic disorder impacted early but not late postnatal mortality. In addition, postnatal mortality both before the age of 1 month or before the age of 1 year was significantly associated with lower postmenstrual age at birth, CHD severity score B and major ECA at birth. These results underscore the importance of genotyping and of accurate cardiac and extracardiac phenotyping for prognostication in fetuses with CHD.

Purpose Whereas noninvasive prenatal screening for aneuploidies is widely implemented, there is an increasing need for universal approaches for noninvasive prenatal screening for monogenic diseases. Here, we present a cost-effective, generic cell-free fetal DNA (cffDNA) haplotyping approach to scan the fetal genome for the presence of inherited monogenic diseases. Methods Families participating in the preimplantation genetic testing for monogenic disorders (PGT-M) program were recruited for this study. Two hundred fifty thousand single-nucleotide polymorphisms (SNPs) captured from maternal plasma DNA along with genomic DNA from family members were massively parallel sequenced. Parental genotypes were phased via an available genotype from a close relative, and the fetal genome-wide haplotype and copy number were determined using cffDNA haplotyping analysis based on estimation and segmentation of fetal allele presence in the maternal plasma. Results In all families tested, mutational profiles from cffDNA haplotyping are consistent with embryo biopsy profiles. Genome-wide fetal haplotypes are on average 97% concordant with the newborn haplotypes and embryo haplotypes. Conclusion We demonstrate that genome-wide targeted capture and sequencing of polymorphic SNPs from maternal plasma cell-free DNA (cfDNA) allows haplotyping and copy-number profiling of the fetal genome during pregnancy. The method enables the accurate reconstruction of the fetal haplotypes and can be easily implemented in clinical practice.

Joris Veltman and colleagues apply exome sequencing to identify heterozygous de novo mutations in SETBP1 as the cause of Schinzel-Giedion syndrome, a rare sporadic disorder characterized by severe intellectual disability and multiple congenital malformations. Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.

Bernard Keavney, Judith Goodship and colleagues report a genome-wide association study of congenital heart disease and identify a region on chromosome 4p16 associated with risk of atrial septal defect. We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated ( P = 9.5 × 10 −7 ) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort ( N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10 −5 ; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19–1.65; combined P = 2.6 × 10 −10 ). Genotype accounted for ∼9% of the population-attributable risk of ASD.

Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3–31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets.

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC.

Purpose: The Ehlers–Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility. Methods: We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition. Results: We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients. Conclusion: This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS. Genet Med 18 9, 882–891.

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.

Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5′ untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR1 mutation and reveal an unexpected nuclear export function for the C‐terminus of FMRP. We screened a cohort of patients with typical FXS symptoms who tested negative for CGG repeat expansion in the FMR1 locus. In one patient, we identified a guanine insertion in FMR1 exon 15. This mutation alters the open reading frame creating a short novel C‐terminal sequence, followed by a stop codon. We find that this novel peptide encodes a functional nuclear localization signal (NLS) targeting the patient FMRP to the nucleolus in human cells. We also reveal an evolutionarily conserved nuclear export function associated with the endogenous C‐terminus of FMRP. In vivo analyses in Drosophila demonstrate that a patient‐mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes. Synopsis A novel point mutation in the FMR1 gene was identified in a typical fragile X syndrome patient, suggesting that undiagnosed FXS patients with single point mutations may exist. Functional analysis shows an unexpected nuclear export role for the prematurely truncated protein. Sequencing of a patient with typical FXS features reveals a point mutation in the FMR1 gene. The resulting FMRP protein encodes a frameshifted sequence resulting in a nuclear/nucleolar localization signal and truncation of the C‐terminal region of FMRP. Mutating the ectopic nucleolar localization signal or restoring the C‐terminus of the human protein results in normal FMRP sub‐cellular localization. Overexpression of a patient‐mimicking protein in Drosophila neurons in vivo causes nuclear localization and novel axonal growth and guidance phenotypes. Restoration of the C‐terminus rescues the localization and the normal activity of Drosophila FMRP. Graphical Abstract A novel point mutation in the FMR1 gene was identified in a typical fragile X syndrome patient, suggesting that undiagnosed FXS patients with single point mutations may exist. Functional analysis shows an unexpected nuclear export role for the prematurely truncated protein.

Wolf–Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf–Hirschhorn syndrome facial phenotype.