In the last few years, trio-Whole Exome Sequencing (WES) analysis has revolutionized the diagnostic process for patients with rare genetic syndromes, demonstrating its potential even in non-specific ...clinical pictures and in atypical presentations of known diseases. Multiple disorders in a single patient have been estimated to occur in approximately 2–7.5% of diagnosed cases, with higher frequency in consanguineous families. Here, we report the clinical and molecular characterisation of eight illustrative patients for whom trio-WES allowed for identifing more than one genetic condition. Double homozygosity represented the causal mechanism in only half of them, whereas the other half showed peculiar multilocus combinations. The paper takes into consideration difficulties and learned lessons from our experience and therefore supports the powerful role of wide analyses for ascertaining multiple genetic diseases in complex patients, especially when a clinical suspicion could account for the majority of clinical signs. It finally makes clear how a patient’s “deep phenotyping” might not be sufficient to suggest the presence of multiple genetic diagnoses but remains essential to validate an unexpected multilocus result from genetic tests.
Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile ...cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient's critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients' clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.
Background
In the last few years trio‐whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical ...presentations of known diseases. Moreover WES allows the detection of variants in multiple genes causing different genetic conditions in a single patient, in about 5% of cases. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition.
Methods
Trio‐WES was performed on a 4‐month‐old baby with a complex clinical presentation characterized by skeletal anomalies, congenital heart malformation, congenital hypothyroidism, generalized venous and arterial hypoplasia, and recurrent infections.
Results
WES detected two different homozygous variants, one in CEP57, the gene responsible for mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short‐rib thoracic dysplasia.
Conclusion
The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants.
The report then highlights the role of WES in providing complete and fast diagnosis in patients with complex presentations of rare genetic syndromes, with important implications in the assessment of recurrence risk.
Whole exome sequencing (WES) allows the detection of variants in multiple genes causing different genetic conditions in a single patient. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition. Trio‐WES was performed in a 4 months patient with complex clinical presentation, and detected two different homozygous variants, one in CEP57, the gene responsible of mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short‐rib thoracic dysplasia. The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants.
Interstitial deletions of chromosome 11 long arm are rarely observed and the associated phenotype ranges from normal to severe, depending on the position and size of the deletion and on the presence ...of unmasked recessive genes on the normal homologous. To our knowledge 32 cases are reported in literature with three family cases. Phenotype-genotype correlation is not very clear and the most common features are characteristic facial dysmorphisms, palate anomalies and developmental delay. Growth retardation is not typical and other major malformations are reported in some cases.
We described a child with 11q interstitial deletion diagnosed at birth with hypotonia and minor dysmorphisms using standard cytogenetic techniques; array CGH was subsequently performed to define the deletion at a molecular level.
This case gave us the opportunity to attempt a genotype-phenotype correlation reviewing the literature and to describe a rehabilitative program that improved the development perspectives of this child.
The mitral valve is often structurally abnormal in hypertrophic cardiomyopathy (HCM). However, the mechanisms responsible for these abnormalities remain controversial. In 2016 we identified, at ...myectomy, muscular mitral-aortic discontinuity in 5 young patients with obstructive HCM.
This study sought to confirm our preliminary findings and assess the prevalence of muscular mitral-aortic discontinuity in obstructive HCM.
At our center, from January 2017 to April 2018, the area between the anterior mitral leaflet and aortic valve was inspected at myectomy in 106 consecutive patients with HCM.
Muscular mitral-aortic discontinuity was identified in 28 (26%) patients and was significantly more common in younger than older patients (age 39 ± 13 years vs. 58 ± 11 years; p < 0.001). Muscular discontinuity was present in each of 6 patients aged <30 years but only 1 (2.7%) of 37 aged ≥60 years. Pathogenic sarcomere mutations were identified in 22 (79%) of 28 patients with and 24 (31%) of 78 without discontinuity (p < 0.001) and were associated with discontinuity independently of age (p = 0.021). Discontinuity mean length was 7.3 mm and was inversely related to age (p = 0.022). At echocardiography, the anterior mitral leaflet was longer in patients with than those without discontinuity (34 ± 4 mm vs. 29 ± 5 mm; p < 0.001).
We report, for the first time, muscular mitral-aortic discontinuity in HCM. At myectomy, a long muscular discontinuity displaced the anterior mitral leaflet toward the apex in most young patients, was significantly associated with sarcomere mutations independent of age, and was extremely uncommon in older patients. These findings suggest that a long muscular mitral-aortic discontinuity could predispose to the development of outflow obstruction in young patients with sarcomere mutations.
Post‐zygotic mosaicism is a well‐known biological phenomenon characterized by the presence of genetically distinct lineages of cells in the same individual due to post‐zygotic de novo mutational ...events. It has been identified in about 13% of Cornelia de Lange (CdLS) syndrome patients with a molecular diagnosis, an unusual high frequency. Here, we report the case of a patient affected by classic CdLS harboring post‐zygotic mosaicism for two different likely pathogenic variants at the same nucleotide position in NIPBL. Double somatic mosaicism has never been reported in CdLS and only rarely recognized in human diseases. Possible pathogenetic mechanisms are discussed.
Abstract
Background
Arrhythmogenic cardiomyopathy is a genetically-inherited cardiomyopathy. PKP2 mutations are the most common cause of the disease, associated with conventional ARVC phenotype.
Case ...presentation
We presented a 14 years old sportswoman admitted to our emergency department for cardiac arrest-related to ventricular fibrillation. The patient was asymptomatic leading up to cardiac arrest. At admission, she met the diagnosis of AC with bi-ventricular involvement (T negative waves in V1-V6 and inferior leads; severe biventricular dysfunction with fibrofatty replacement involving both ventricles). Family history revealed that her cousin, a 15 years competitive athlete, received a recent diagnosis of ARVC, wherein pathogenetic variant p.Tyr857_Lys859 in heterozygosity in the PKP2 gene was found. As expected, the index case presented the same mutations in PKP2 gene, and no other mutations were found. Implanted cardioverter defibrillator (ICD) and strength follow-up, including heart failure management, was performed. Cascade screening of family members allowed us to identify 19 mutations carriers. Of these, 5 patients were identified to have disease expression. The first to be studied was her 9 years old sister, who involved in high level of sport activities. She presented abnormal ECG with negative T waves in V2-V4, significance burden of premature ventricular complex (PVC >500/24 h) with mild right ventricle dilatation. Of others family members, four patients presented early signs of myocardial disease and significant arrhythmias burden. Except for one patient, all these members were involved in amateur sport activities. Two members had signs of left ventricle (LV) involvement (inverted T waves in leads V4–V6 and inferior leads, LV wall motion abnormalities and late enhancement), whereas one patient (P3) showed a fulfilled ARVD. Three patients presented significant PVC on 24-hour ambulatory ECG monitoring (PVC >500/24 h) (P2, P3 and P5). The arrhythmic burden was more pronounced in two young patients having a sports activity (P2 and P3). This trend was also confirmed at exercise testing. Except for one patient, these findings appear to be related to sport activity, even if this is no high-intensity activity. Among other carriers of pathogenic mutation, three patients showed ECG abnormalities in infero-lateral leads and significance PVC at 24-hour ECG monitoring in absence of other findings related-cardiomyopathy. All family members carried PKP2 mutation were restricted in sports activities, and, in patients presented early disease and arrhythmogenic burden, treatment with beta-blockers was started.
Conclusion
In this family presenting PKP2 mutation, heterogenicity of disease expression and a close relationship with sport activity was found. This large family case encourages future ACM studies to better understand disease expression and their relationship with sports activity across the entire ACM phenotypic spectrum and ages. Also, this case underscores the importance of early familiar screening, including children involved high-level of sports activity.
DYRK1A‐related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which ...let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable.
Abstract
Mesenchymal hamartoma of the liver (MHL) is rare. Less than 50 adult cases have been described. Due to their potential degeneration or recurrence, a complete surgical resection must be ...performed. We describe a case of a 26-year-old with a palpable solid lesion, which displaced abdominal organs. Percutaneous needle biopsies suggested the diagnosis of MHL. A right hemi-hepatectomy without segment 1 was performed; the post-operative course was uneventful. The mesenchymal component of the tumour was reactive to desmin and smooth muscle actin. Low proliferation index was confirmed (MIB1). Genetic counselling: the sequencing analysis of DICER1 and CDKN1C gene was negative, DNA methylation analysis on the chromosome 11p15 region was normal. After 42 months, there was no recurrence. In conclusion, clinicians should consider MHL in the differential diagnosis. The dimension and the need of radicality impose major liver resections or liver transplantations, which should be performed in referral centres.
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of ...genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.
We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.
We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.
Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
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