Sergio Fini

Molecular strategies in genetic diagnosis of transthyretin-related hereditary amyloidosis.

Transthyretin‐related hereditary (TTR) amyloidoses represent a clinically heterogeneous group of diseases associated with various point mutations of the TTR gene. We propose a molecular strategy for the diagnosis of this group of disorders.— Ferlini, A.; Fini, S.; Salvi, F.; Patrosso, M. C.; Vezzoni, P.; Forabosco, A. Molecular strategies in genetic diagnosis of transthyretinrelated hereditary amyloidosis. FASEB J. 6: 2864‐2866; 1992.

New patients with Temple syndrome caused by 14q32 deletion: Genotype‐phenotype correlations and risk of thyroid cancer

Temple syndrome (TS) is caused by abnormal expression of genes at the imprinted locus 14q32. A subset of TS patients carry 14q32 deletions of paternal origin. We aimed to define possible genotype‐phenotype correlations and to highlight the prevalence of thyroid dysfunction, which is a previously unreported feature of TS. We described four new patients who carry deletions of paternal origin at 14q32 detected by array‐CGH and reviewed nine patients reported in the medical literature. We compared clinical features with respect to deletion size and position. Expression of DLK1 is altered in all the patients with TS, but intellectual disability (ID) is present only in patients with larger deletions extending proximally to the imprinted locus. This study led to the identification of an ID “critical region” containing four annotated genes including YY1 as the strongest candidate. Furthermore, we described three patients with thyroid dysfunction, which progressed to papillary carcinoma at a very young age in two of them. We conclude that DLK1 loss of function is likely to be responsible for the core features of TS, while haploinsufficiency of a gene outside the imprinted region causes ID. Thyroid cancer may be an unrecognized feature and monitoring for thyroid dysfunction should thus be considered in TS patients.

Transcriptional behavior of DMD gene duplications in DMD/BMD males

DMD gene exons duplications account for up to 5–10 % of Duchenne (DMD) and up to 5–19% of Becker (BMD) muscular dystrophies; as for the more common deletions, the genotype‐phenotype correlation and the genetic prognosis are generally based on the “reading frame rule”. Nevertheless, the transcriptional profile of duplications, abridging the genomic configuration to the eventual protein effect, has been poorly studied. We describe 26 DMD gene duplications occurring in 33 unrelated patients and detected among a cohort of 194 mutation‐positive DMD/BMD patients. We have characterized at the RNA level 16 of them. Four duplications (15%) behave as exception to the reading frame rule. In three BMD cases with out‐of‐frame mutations, the RNA analysis revealed that exon skipping events occurring in the duplicated region represent the mechanism leading to the frame re‐establishment and to the milder phenotype. Differently, in a DMD patient carrying an in‐frame duplication the RNA behaviour failed to explain the clinical phenotype which is probably related to post‐transcriptional‐translational mechanisms. We conclude that defining the RNA profile in DMD gene duplications is mandatory both for establishing the genetic prognosis and for approaching therapeutic trials based on hnRNA modulation.

Mutation Load of Multiple Ion Channel Gene Mutations in Brugada Syndrome

Brugada syndrome is a primary arrhythmic syndrome that accounts for 20% of all sudden cardiac death cases in individuals with a structurally normal heart. Pathogenic variants associated with Brugada syndrome have been identified in over 19 genes, with SCN5A as a pivotal gene accounting for nearly 30% of cases. In contrast to other arrhythmogenic channelopathies (such as long QT syndrome), digenic inheritance has never been reported in Brugada syndrome. Exploring 66 cardiac genes using a new custom next-generation sequencing panel, we identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient. The parents were heterozygous for each variation. This novel finding highlights the role of mutation load in Brugada syndrome and strongly suggests the adoption of a gene panel to obtain an accurate genetic diagnosis, which is mandatory for risk stratification, prevention, and therapy.

Genetic counseling for women referred for advanced maternal age: a telegenetic approach.

To the Editor: Medical genetics and genetic counseling represent vital tools for communicating with patients about genetic risk, reproductive options, prenatal testing, and novel therapies. Medical geneticists and genetic counselors are the professionals in charge of genetic diagnosis and risk evaluation, representing the most important resource for communicating to patients all issues related to genetic diseases (both rare and common). There is a general consensus, promoted by the Eurogentest Network of Excellence (http://www.eurogentest.org), that genetic counseling should be a mandatory accompaniment to all medical genetics interventions. This becomes particularly relevant with the advent of high-throughput diagnosis, including noninvasive prenatal testing. Indeed, despite the potential for rapid results, the need for counseling delivered by expert geneticists must not be overlooked, and the issues surrounding data filtering and validation need to be addressed. This entails providing access to genetic counseling at various points within the health-care system, which will inevitably impact both national and local policy making. In the current economic climate, the medical geneticist is a relatively marginal figure, often restricted to a few specialist centers, even in countries of the European Union. Patients who are affected by rare diseases have the right to benefit from expert assistance in their clinical management, diagnosis, and care, no matter where they are or the rareness of their disease. Through the adoption of telemedical technology in genetics (telegenetics), as encouraged by various EU initiatives, the gap between specialists and patients may more easily be bridged. Multimedia telegenetics tools will enable us to provide interactive genetic consultations from a distance—feasibly to people in other countries—thereby increasing the accessibility of this invaluable service and helping to meet the needs of centers of excellence for rare diseases. According to the World Health Organization, telemedicine is “the delivery of health-care services, where distance is a critical factor, by all health-care professionals using information and communication technologies for the exchange of valid information for diagnosis, treatment and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interests of advancing the health of individuals and their communities.”1 With this in mind, we produced a short digital film on telegenetic counseling for pregnant women of advanced maternal age. Reasoning that the increasing number of women and couples requiring genetic testing, many of whom will not have easy access to counseling centers, need a standardized, reliable approach, we explain the genetic risks associated with advanced maternal age, as well as possible preventive measures, prenatal testing procedures (both invasive and noninvasive), laboratory assessment methods (stating the specificity and accuracy of the available tests), and best-practice communication of results. We also explain any possible causes of test failure and stress the role of the medical geneticist and the importance of effective communication during genetic counseling. This video is freely available in both English and Italian (www.ospfe.it/geneticamedica). It is our hope that this initiative will facilitate communication among geneticists, obstetricians, pregnant women, and all stakeholders involved in prenatal care and diagnosis.

Double Interstitial Deletion of the Long Arm of Chromosome 6 in a Patient with Pierre Robin Sequence, Dysmorphisms, and Severe Developmental Delay

Reported here is the case of a 1.8-year-old boy with a 9.6- Mb deletion in 6q13q14.1 and an 11.2-Mb deletion in 6q21q22.31, ascertained through array CGH, as the result of a complex de novo chromosome rearrangement. The clinical picture of this patient is characterized by severe psychomotor delay, dysmorphic features, and some congenital defects. Although, as reported in the literature, phenotypes associated with 6q deletions may vary, an attempt was made to associate the patients symptoms to either deletion, comparing them to previously reported cases. Only a limited specific correlation was found, probably due to the prevalence of very common symptoms.

A New 3p14.2 Microdeletion in a Patient with Intellectual Disability and Language Impairment: Case Report and Review of the Literature

Interstitial deletions of chromosome 3p are rare, and specific genotype-phenotype correlations cannot always be assessed. We report the case of a 3p14.2 proximal microdeletion in a 60-year-old female patient with mild intellectual disability, severe speech delay, and mild dysmorphism. An array-CGH analysis detected a 500-kb deletion in the 3p14.2 region, including FEZF2, CADPS, and PTPRG. FEZF2 and CADPS are known to network within the neurodevelopmental pathways. It is possible that their rearrangements lead to the phenotypic features observed in the patient, and therefore, they can be considered candidate genes responsible for such abnormalities.