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–phenotype correlations.
Three hundred fifty-two chromosomal microarray–negative 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.
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 ≥2 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.
After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic ...deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue‐ and temporal‐specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent‐of‐origin effect.
Synopsis
Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.
Two rare variants of maternal origin (an intragenic deletion and a missense change) were identified in CADPS2 in a cohort of patients with neurodevelopmental abnormalities; the p. Asp1113Asn variant was shown to disrupt the interaction with dopamine receptor type 2 (D2DR).
Differentially methylated sites were identified in CADPS2 first intron, in blood and amygdala, but they did not show a parent‐of‐origin methylation pattern typical of an imprinted gene.
Tissue‐specific, monoallelic maternal expression of CADPS2 in blood and in the amygdala plays a key role in regulating social interactions and supports the importance of a fine modulation of CADPS2 for human behavior.
CADPS2 variants may contribute to intellectual disability and autism susceptibility, and their role should be interpreted in light of possible parent‐of‐origin effect.
Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background and Aims
Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of the purine metabolism which results in the conversion of adenine into 2,8 ...dihydroxyadenine (DHA) due to the activity of the xanthine oxidoreductase (XOR). Patients affected by APRT deficiency if not treated with inhibitors of XOR may develop 2,8-DHA nephropathy that might progress to end-stage kidney disease (ESKD) with the need of kidney transplant. The high rate of misdiagnosis of 2,8-DHA nephropathy in native kidneys could lead to the failure of kidney graft in transplanted patients affected by APRT deficiency.
Method
Here, we report the case of a female, 63-years old patient with ESKD of unknown cause on regular hemodialysis treatment from 2018 after a period of three years on peritoneal dialysis, who underwent kidney transplantation in our Center in 2022. Her medical history showed a metabolic syndrome. She did not experience episodes of renal colic whereas family history reported a brother affected by frequent renal colic of unknown cause. In March 2022, she underwent kidney transplantation from a deceased death brain donor. Induction therapy includes basiliximab, tacrolimus, mycophenolic acid and steroids. Due to the persistence of delay graft function, ten days after kidney transplantation an allograft biopsy has been performed. The histological examination revealed tubular damage surrounded by inflammation cells and intratubular crystals in the renal cortex. The crystals were reddish brown tinged in hematoxylin and eosin stain and were birefringent under polarized light Fig. 1 A, B, so they were strongly related to the hypothesis of DHA crystals. Consistently, the urinalysis showed yellow-brown crystals of DHA. Thus, a genetic analysis of APRT gene has been performed showing two novel heterozygous variants c.388_397p.(Leu130ValfsTer4) and exon 3 deletion, expected pathogenic. The patient was treated with bolus of methylprednisolone (4mg/kg alternate to 50 mg) and a therapy with febuxostat 80 mg/die was started to reduce the amount of plasma DHA. In addition, based on our previous experience of recurrence DHA nephropathy after transplantation, we treated the patient with six consecutive hemodiafiltration (HDF) sessions without ultrafiltration, to promptly remove the serum DHA avoiding their precipitation in the graft while waiting for the lowering effect of febuxostat. At discharge the patient showed an increase of the urine output not associated with a complete recovery of kidney function (sCr 3.88 mg/dl, uric acid 1.6 mg/dl), so two other hemodialysis treatments were performed in the next two weeks.
Results
At present, almost one year after kidney transplant, the patient is doing well and the graft function is stable with a sCr of 1.6 mg/dl without significant presence of DHA crystals in the urine.
Conclusion
In conclusion, we find out an unexpected recurrence of 2,8-DHA nephropathy due to novel expected pathogenetic variants of APRT gene in patient without medical history of kidney stones successfully treated with steroid, febuxostat and hemodiafiltration.
The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial ...tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor‐β (TGF‐β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF‐β signaling. More recently, TGF‐β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF‐β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF‐β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
Mutations in TGFBR1/2, TGFB2/3 and SMAD2/3 cause Loeys‐Dietz syndrome (LDS), a connective tissue disorder affecting the cardiovascular, skeletal and ocular system. This review highlights known and novel SMAD2/3 and TGFB2/3 mutations and compares the clinical features of affected individuals with those reported in the literature, hereby extending the spectrum of phenotypes associated with these LDS genes. This confirms that LDS is a disorder with a broad phenotypical spectrum that is still emerging as more patients are identified.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In heritable aortic diseases, different vascular involvement may occur with potential variable implications in aortic dilation/dissection risk. This study aimed to analyze the aortic anatomy of ...individuals with Marfan syndrome and Loeys-Dietz syndrome to identify possible morphological differences.
Computed tomography and magnetic resonance imaging of the thoracoabdominal aorta from the proximal supra-aortic vessels to the femoral bifurcation level of 114 patients with Marfan and Loeys-Dietz syndromes and 20 matched control subjects were examined. Aortic diameters, areas, length, and tortuosity were measured in different aortic segments using specific vessel analysis software.
Patients with Marfan syndrome showed a higher prevalence of ascending aorta and aortic root dilation (P = .011), larger and longer aortic roots (P = .013) with pear-shaped phenotype, larger isthmus/descending aorta diameter ratio (P = .015), and larger suprarenal aorta and iliac arteries. Patients with Loeys-Dietz syndrome showed longer indexed segments and a significantly longer arch (P = .006) with type 2/3 arch prevalence (P = .097). Measurement ratios analysis provided cut-off values (aortic root to ascending aorta length/aortic root diameter, aortic root/sinotubular junction, aortic root/ascending aorta diameter) differentiating patients with Marfan syndrome from patients with Loeys-Dietz syndrome, even in the early stage of the disease.
Both syndromes show peculiar anatomic patterns at different aortic levels irrespective of aortic dilation and disease severity. These features may represent the expression of different genetic mutations on aortic development, with a potential impact on prognosis and possibly contributing to better management of the diseases. The systematic adoption of whole body imaging with magnetic resonance or computed tomography should always be considered, because they allow a complete vascular assessment with practical indicators of differential diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
To establish the positive predictive values (PPV) of cfDNA testing based on data from a nationwide survey of independent clinical cytogenetics laboratories.
Methods
Prenatal diagnostic ...test results obtained by Italian laboratories between 2013 and March 2020 were compiled for women with positive non‐invasive prenatal tests (NIPT), without an NIPT result, and cases where there was sex discordancy between the NIPT and ultrasound. PPV and other summary data were reviewed.
Results
Diagnostic test results were collected for 1327 women with a positive NIPT. The highest PPVs were for Trisomy (T) 21 (624/671, 93%) and XYY (26/27, 96.3%), while rare autosomal trisomies (9/47, 19.1%) and recurrent microdeletions (8/55, 14.5%) had the lowest PPVs. PPVs for T21, T18, and T13 were significantly higher when diagnostic confirmation was carried out on chorionic villi (97.5%) compared to amniotic fluid (89.5%) (p < 0.001). In 19/139 (13.9%), of no result cases, a cytogenetic abnormality was detected. Follow‐up genetic testing provided explanations for 3/6 cases with a fetal sex discordancy between NIPT and ultrasound.
Conclusions
NIPT PPVs differ across the conditions screened and the tissues studied in diagnostic testing. This variability, issues associated with fetal sex discordancy, and no results, illustrate the importance of pre‐ and post‐test counselling.
Key points
What's already known about this topic?
The reported performance of cfDNA testing by NIPT laboratories is often based on incomplete follow‐up.
Data from cytogenetics laboratories can provide an alternative, independent, assessment on the positive predictive value (PPV), risk in cases when there is no result, and help explain contradictory fetal sex assignments.
Prior cytogenetic laboratory studies assessing PPV from have been based on small numbers of cases.
What does this study add?
PPV is higher when the diagnostic testing is based on CVS compared to amniocentesis, presumably because CVS includes cases with confined placental mosaicism.
In a high proportion of no result cases, a cytogenetic abnormality may be present. Therefore, these do need to be considered high‐risk pregnancies.
Diverse disorders of sexual development can be present when fetal sex assignments based on ultrasound and NIPT are discordant.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
(Abstracted from
Prenat Diagn
2022;42:1575–1586
Methods for diagnosis of genetic abnormalities have recently undergone substantial improvement. Noninvasive prenatal testing (NIPT) is performed early ...in pregnancy, typically at the end of the first trimester using cell-free DNA (cfDNA) to identify 3 commonly occurring trisomies (13, 18, and 21).
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