Pathophysiology of coarctation of aorta in dichorionic twins with growth discordance

Coarctation of the aorta (CoA) is an abnormal narrowing of the aorta which can occur as an isolated defect or in association with other intracardiac anomalies, in syndromic and non-syndromic patients, with a prevalence of 4 per 1000 live births1. CoA represents a challenge in prenatal diagnostics, and its pathophysiological mechanisms are not well-understood. We report on four dichorionic diamniotic twin pairs presenting with CoA and fetal growth restriction (FGR) in one twin and a discordant phenotype in the cotwin (Table 1)

External hydrocephalus as a prenatal feature of Noonan Syndrome

Brain malformations have been reported in RASopathies, including postnatal external hydrocephalus, a nonobstructive form of cerebrospinal fluid accumulation around the brain. It was described in a few patients with mutations of other genes than PTPN11, such as SOS1 and SHOC2 and never in prenatal diagnosis. The aim of this case report is to describe the prenatal presentation of a fetus with Noonan syndrome (NS) and external hydrocephalus. We report on a Noonan syndrome fetus with a de novo pathogenic PTPN11 c.923A>G p.Asn308Ser mutation, showing external hydrocephalus, an extremely rare fetal finding, corpus callosum, and cerebellar vermis under the 10th centile, plus a typical NS cardiopathy. This is the first case of Noonan syndrome prenatal diagnosis in a fetus presenting with external hydrocephalus. Following pathophysiological considerations, we suggest to consider NS in the differential diagnosis of external hydrocephalus, investigating other evocative findings and considering molecular screening for mutations in NS-related genes

Myoclonic epilepsy. case report of a mild phenotype in a pediatric patient expanding clinical spectrum of kcna2 pathogenic variants

We report on the rare case of a male toddler presenting with myoclonic epilepsy characterized by daily episodes of upward movements of the eyebrows, and myoclonic jerks of both head and upper limbs. In addition, the child showed speech delay, tremors, and lack of motor coordination. Next Generation Sequencing analysis (NGS) performed in trio revealed in the proband the c.889C>T de novo missense variant in the KCNA2 gene in heterozygous state. This is the first case of myoclonic epilepsy in a toddler due to a c.889C>T KCNA2 missense variant. The patient was treated with valproic acid and ethosuximide with a good clinical response. At 6 years old, follow-up revealed that the proband was seizure-free with tremors and clumsiness in movements. According to the literature, this case supports the correlation between myoclonic epilepsy and KCNA2 alterations. This evidence suggests that performing genomic testing including the KCNA2 gene in preschool patients affected by myoclonic epilepsy, especially when associated with delayed neurodevelopment. Our goal is to expand the phenotypical spectrum of this rare condition and adding clinical features following a genotype-first approach

A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) is a rare autosomal recessive neuromuscular disorder characterized by arthrogryposis multiplex congenita and prenatal fractures of the long bones, with poor prognosis. The most affected patients present with biallelic loss-of-function nucleotide variants in ASCC1 gene, coding a subunit of the transcriptional coactivator ASC-1 complex, although the exact pathogenesis is yet unknown. This work describes the first case of SMABF2 in a stillbirth with documented evolution of the disease in the prenatal period. A microdeletion copy number variant (CNV) of about 64 Kb, involving four exons of ASCC1, was firstly detected by microarray analysis, requested for arthrogryposis and hydrops. Subsequent exome analysis disclosed a nucleotide variant of the same gene [c.1027C>T; (p. Arg343*)], resulting in the introduction of a premature termination codon. This stillbirth represents the first case of ASCC1 compound heterozygosity, due to an exonic microdeletion and a nucleotide variant, expanding the mutational spectrum of this gene. It also provides further evidence that exonic CNVs are an underestimated cause of disease-alleles and that the integrated use of the last generation genetic analysis tools, together with careful clinical evaluations, are fundamental for the characterization of rare diseases even in the prenatal setting

Small 7p22.3 microdeletion: case report of Snx8 haploinsufficiency and neurological findings

Some cases of chromosome 7p22.3 deletions have been reported, but the genotype-phenotype correlation is still uncertain. Neurodevelopmental delay and heart anomalies have been recorded as the most recurrent defects. We describe the clinical features of a four-year-old male child with a 139 kb deletion at 7p22.3 involving SNX8 gene, inherited from a mosaic mother. The same deletion is also present in the fetus on the ongoing third pregnancy of the couple with normal fetal ultrasound assessment. The proband was prenatally diagnosed with left kidney agenesis. He does not show any congenital heart disease, but mild intellectual disability, learning and language delay, and severe behavioral problems related to the hyperactive-impulsive and inattentive area. These clinical features are also evident in other 7p22 deletions cases involving the SNX8 gene, supporting the role of this gene in neurodevelopment. Conversely, the revision of all published cases with small 7p22 deletions and the absence of heart malformations in the present family confirm that this region is involved in heart development, anyway did not confirm the role of SNX8 in cardiac phenotypes, either due to the reduced penetrance or the involvement of other candidate genes

Coexisting genetic findings in a cohort of patients with laboratory confirmation of 22q11.2 deletion syndrome

22q11.2DS is the most common microdeletion disorder, affecting ~ 1:3000-6000 live births, characterized by high phenotypic variability with multiorgan involvement With the advent of WGS, the diagnosis of multiple genetic disorders in a single individual is becoming more widely recognized (~ 4-6%) In patients who already have a genetic diagnosis, a secondary genetic disorder can be found as an explanation for clinical features atypical for the known genetic anomaly Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations on the other allele unmasking autosomal recessive conditions The presence of a dual diagnosis may exacerbate symptoms and impacts clinical management Our study showed a remarkable prevalence of coexisting genetic anomalies in patients with 22q11.2 DS or 22q11.2DuplS Indication for genome-wide microarray in lieu of MLPA or FISH, especially in patients with atypical findings for the 22q11.2 deletion/duplication syndrome or with familial recurrence of other genetic conditions Interestingly, in our cohort, 2 patients present a second anomaly affected the function of a gene that regulates cells proliferation (NF1 and RET), resulting in a predisposition of developing tumors and maybe genetic fragility Accurate diagnosis of a additional genetic conditions allows for more appropriate and personalized medical management and for suitable genetic counseling of families

Uniparental disomy of chromosome 16: a case report with a new cardiac malformation Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: e-Posters

Introduction: Maternal uniparental disomy of chromosome 16 [UPD(16)mat] is the most often reported UPD other than UPD(15). In literature there is not a specific phenotype associated with upd(16)mat and few follow-up data are reported. Materials and methods: We present the case of a 1-y.o. male of a healthy non-consanguineous parents. In prenatal diagnosis IUGR, polydramnios and single umbilical artery was reported. He born late preterm, small for gestational age, and showed facial dysmorphisms and congenital malformations (esophageal atresia, cardiac defects, mild bone alterations, hypospadias). Transesophageal echocardiography detected persistency of left superior vena cava draining into the left atrium through an unroofed coronary sinus. Brain ultrasound showed dilated and asymmetric lateral ventricles. At present, cognitive and language abilities are adequate for age but he has mild gross motor delay. Genomic DNA was extracted from peripheral blood and analyzed by SNP-array (Cytoscan HD; Thermo Fisher Scientific). Results: SNP-array analysis showed a 147 Kb homozygous 16p13.3 microdeletion and a 114 kb 16q24.3 microtriplication, both segregated from the mother. Region of Homozigosity (ROH) analysis showed two ROH of 7 and 13 Mb on chromosome 16 compatible with the presence of UPD(16) of maternal origin. The possible presence of a residual mosaic trisomy 16 was excluded by karyotype analysis and FISH. Conclusions: This is an additional case of the phenotypic characterization of UPD(16)mat. To date, it is the first time that an unroofed coronary sinus is described within cardiac malformations associated with UPD(16)mat. Moreover, according to literature data, it confirms the need to extend follow-up

When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort

Purpose: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype\u2013phenotype correlations. Methods: Three hundred fifty-two chromosomal microarray\u2013negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons. Results: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or 652 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM. Conclusion: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association