Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the <i>MEF2C</i> gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without <i>MEF2C</i> involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve <i>MEF2C</i> but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a <i>TBX22</i> gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.

Clinical importance of left atrial infiltration in cardiac transthyretin amyloidosis

Funding Acknowledgements Type of funding sources: None. INTRODUCTION The clinical significance of left atrial (LA) involvement in ATTR amyloidosis cardiomyopathy (ATTR-CM) has not been characterized. The aims of this study were to characterize: (1)LA pathology in explanted ATTR-CM hearts; (2)LA mechanics using echocardiographic speckle-tracking in a large cohort of ATTR-CM patients; (3)to study the association with mortality. METHODS AND RESULTS Congo red staining and immunohistochemistry was performed to assess the presence, type and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle-tracking was used to assess LA reservoir, conduit, contractile function and stiffness in 906 ATTR-CM patients (551 wt-ATTR-CM;93 T60A-ATTR-CM;241 V122I-ATTR-CM;21 other). There was extensive ATTR amyloid infiltration in the 5 atria with loss of normal architecture, vessels remodelling, capillary disruption and subendocardial fibrosis. Echo speckle-tracking in 906 ATTR-CM patients demonstrated increased atrial stiffness [median(25th-75th quartile) 1.83(1.15-2.92)] that remained independently associated with prognosis, after adjusting for known predictors (lnLA stiff:HR = 1.26,CI 1.07-1.57;p = 0.009). There was substantial impairment of the three phasic functional atrial components [reservoir 8.86(5.94-12.97)%; conduit 6.5(4.53-9.28)%; contraction function 4.0(2.29-6.56)%]. Atrial contraction was absent in 21.6% of patients whose ECG showed sinus rhythm (SR)-"atrial electro-mechanical dissociation"(AEMD). AEMD was associated with poorer prognosis compared to SR patients with effective mechanical contraction (p &lt; 0.0001). AEMD conferred a similar prognosis to patients in AF. CONCLUSION The phenotype of ATTR-CM includes significant infiltration of the atrial walls with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis. Abstract Figure.

Ring Chromosome 20 Syndrome: Genetics, Clinical Characteristics, and Overlapping Phenotypes

Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in a mosaic state and is diagnosed by means of karyotyping. r(20) syndrome is characterized by a recognizable epileptic phenotype with typical EEG pattern, intellectual disability manifesting after seizure onset in otherwise normally developing children, and behavioral changes. Despite the distinctive phenotype, many patients still lack a diagnosis—especially in the genomic era—and the pathomechanisms of ring formation are poorly understood. In this review we address the genetic and clinical aspects of r(20) syndrome, and discuss differential diagnoses and overlapping phenotypes, providing the reader with useful tools for clinical and laboratory practice. We also discuss the current issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies. Ultimately, we explore future perspectives of r(20) research. Our intended audience is clinical and laboratory geneticists, child and adult neurologists, and genetic counselors.

Congenital immobility and stiffness related to biallelic ATAD1 variants

ObjectiveTo delineate the phenotype associated with biallelic ATAD1 variants.MethodsWe describe 2 new patients with ATAD1-related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients.ResultsPatients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both had absent brainstem evoked auditory responses (BEARs). Patient 1 carried the homozygous p.(His357Argfs*15) variant in ATAD1. In the light of the finding in patient 1, a second reading of exome data for patient 2 revealed the novel homozygous p.(Gly128Val) variant.ConclusionsAnalysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic ATAD1 mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.

Aß 40 Mutants Protect Drosophila Against aß 42 Toxicity Despite Their Amyloidogenic Properties in the Non-transgenic Mouse Brain

BackgroundSelf-assembly of the amyloid-β (Aβ) peptide into aggregates, ranging from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However it is clear that not all forms of Aβ are equally harmful, and that linking a specific aggregate to toxicity also depends on the assays and model systems used [1, 2]. Indeed, though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration.MethodsIn this study we utilized BRI2-Aβ fusion technology and rAAV2/1 based somatic brain transgenesis to examine Aβ aggregates that form from selective expression of individual mutant Aβ species in vivo. In parallel we generated PhiC31-based transgenic Drosophila melanogaster expressing WT and mutant Aβ40 and Aβ42, fused to the Argos signal peptide and placed under the GAL4-upstream activation sequence (UAS) expression system in order to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different forms of Aβ40 and Aβ42 species.ResultsWhen expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42 WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of the flies and exacerbated their behavior. In contrast, flies expressing a copy of Aβ40 (wild type [WT] or mutants) in addition to Aβ42 WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40.ConclusionsThese studies suggest that some Aβ40 mutants form unique amyloid aggregates in mouse brains, despite being protective against Aβ42 toxicity in Drosophila, which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

Super-Sweet Purple Sweetcorn: Breaking the Genetic Link

Purple-pericarp supersweet sweetcorn currently does not exist as a horticultural product. Purple pericarp comprises the outer layers of the kernel, with the purple pigment being produced by anthocyanin. Unlike the aleurone layer which can also be pigmented, the pericarp is maternal tissue. Although standard purple sweetcorn based on mutations such as sugary1 (su1) and sugary enhancer (se1) are in existence, the development of purple supersweet sweetcorn based on the widely used shrunken2 (sh2) gene mutation is much more challenging. This is because there is an extremely close genetic linkage between the supersweet shrunken-2 mutation and the anthocyanin biosynthesis gene, anthocyaninless-1 (a1). As distance between these two genes is only 0.1 cM, the development of purple supersweet sweetcorn depends on breaking this close genetic link, which occurs at a very low frequency of 1 in 1000 meiotic crossovers. To make this possible, we crossed a white supersweet variety (a1a1sh2sh2) with a purple-pericarp Peruvian maize (A1A1Sh2Sh2) to obtain an initial heterozygous hybrid (A1a1Sh2sh2). The hybrid seed was sown and subsequently self-pollinated to produce seed segregating for the double recessive homozygote, sh2sh2 (1 in 4). These kernels present a visually distinctive phenotype, characterised by the seed’s shrunken appearance. Approximately 2760 sh2sh2 seeds were separated and resown. Due to the low frequency of linkage breakage, the majority of these plants (~99.9%) produced supersweet white cobs (a1a1sh2sh2). Three plants (0.1%) however, produced supersweet purple cobs (A1a1sh2sh2), due to a single low-frequency linkage break. These cobs will form the basis for a purple-pericarp supersweet sweetcorn breeding program.