Molecular genetics of syndromic and non‐syndromic forms of parathyroid carcinoma

Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non‐syndromic) non‐hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism‐jaw tumor syndrome (HPT‐JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT‐JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ～2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%–40% of patients with sporadic PC and may reveal unrecognized HPT‐JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype–phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT‐JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non‐syndromic (sporadic) forms of PC.     

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

Although whole‐exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM‐referenced genes called “medical exome” (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non‐syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.     

International Society of Neuropathology‐Haarlem Consensus Guidelines for Nervous System Tumor Classification and Grading

Major discoveries in the biology of nervous system tumors have raised the question of how non‐histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro‐oncological specialties. The present “white paper” catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided “ISN‐Haarlem” guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be “layered” with histologic classification, WHO grade and molecular information listed below an “integrated diagnosis”; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro‐oncology; and (iv) entity‐specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.     

Phenotypic heterogeneity and mutational spectrum in a cohort of 45 Italian males subjects with X‐linked ectodermal dysplasia

Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal‐derived structures. X‐linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal‐derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care.     

Next‐generation‐sequencing‐based risk stratification and identification of new genes involved in structural and sequence variations in near haploid lymphoblastic leukemia

Near haploidy (23–29 chromosomes) is a numerical cytogenetic aberration in childhood acute lymphoblastic leukemia (ALL) associated with particularly poor outcome. In contrast, high hyperdiploidy (51–67 chromosomes) has a favorable prognosis. Correct classification and appropriate risk stratification of near haploidy is frequently hampered by the presence of apparently high hyperdiploid clones that arise by endoreduplication of the original near haploid clone. We evaluated next‐generation‐sequencing (NGS) to distinguish between “high hyperdiploid” leukemic clones of near haploid and true high hyperdiploid origin. Five high hyperdiploid ALL cases and the “high hyperdiploid” cell line MHH‐CALL‐2, derived from a near haploid clone, were tested for uniparental isodisomy. NGS showed that all disomic chromosomes of MHH‐CALL‐2, but none of the patients, were of uniparental origin, thus reliably discriminating these subtypes. Whole‐exome‐ and whole‐genome‐sequencing of MHH‐CALL‐2 revealed homozygous non‐synonymous coding mutations predicted to be deleterious for the protein function of 63 genes, among them known cancer‐associated genes, such as FANCA, NF1, TCF7L2, CARD11, EP400, histone demethylases, and transferases (KDM6B, KDM1A, PRDM11). Only eight of these were also, but heterozygously, mutated in the high hyperdiploid patients. Structural variations in MHH‐CALL‐2 include a homozygous deletion (MTAP/CDKN2A/CDKN2B/ANRIL), a homozygous inversion (NCKAP5), and an unbalanced translocation (FAM189A1). Together, the sequence variations provide MHH‐CALL‐2 with capabilities typically acquired during cancer development, e.g., loss of cell cycle control, enhanced proliferation, lack of DNA repair, cell death evasion, and disturbance of epigenetic gene regulation. Poorer prognosis of near haploid ALL most likely results from full penetrance of a large array of detrimental homozygous mutations. © 2013 Wiley Periodicals, Inc.     

R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy

Mutations in the p63 gene have been identified in five types of syndromic ectodermal dysplasias (EDs) with overlapping phenotypes: Ectrodactyly-Ectodermal dysplasia-Clefting (EEC syndrome, MIM 604292), Ankyloblepharon-Ectodermal dysplasia-Clefting (AEC syndrome, MIM 106260) [3], Acro-Dermato-Ungueal-Lacrimal-Tooth (ADULT syndrome, MIM 103285), Rapp-Hodgkin (RHS syndrome, MIM 129400) and Limb-Mammary (LMS syndrome, MIM 603543) [2]. In all those conditions congenital heart defects have been only occasionally found and to date, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) has never been observed in patients affected by p63-related ectodermal dysplasia [9]. Here we describe for the first time this association.     

Ectodermal dysplasias: a new clinical-genetic classification

The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation.The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated "non-ectodermal" features.     

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy,global developmental delay,epilepsy, ataxia,and choreoathetosis

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy‐10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo‐reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate‐to‐pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non‐single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between “syndromic” cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.     

X‐linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia: genotypic‐dental phenotypic findings

Clauss F, Chassaing N, Smahi A, Vincent MC, Calvas P, Molla M, Lesot H, Alembik Y, Hadj‐Rabia S, Bodemer C, Manière MC, Schmittbuhl M. X‐linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia: genotypic‐dental phenotypic findings. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of ectodermal structures and its molecular etiology corresponds to mutations of EDA‐EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4–20) to 22.5 (10–28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub‐domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA‐EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA‐EDAR genes during odontogenesis. The present genotypic‐phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA‐NF‐k B in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.     

Elements of morphology: Standard terminology for the teeth and classifying genetic dental disorders

Dental anomalies occur frequently in a number of genetic disorders and act as major signs in diagnosing these disorders. We present definitions of the most common dental signs and propose a classification usable as a diagnostic tool by dentists, clinical geneticists, and other health care providers. The definitions are part of the series Elements of Morphology and have been established after careful discussions within an international group of experienced dentists and geneticists. The classification system was elaborated in the French collaborative network “TÊTECOU” and the affiliated O‐Rares reference/competence centers. The classification includes isolated and syndromic disorders with oral and dental anomalies, to which causative genes and main extraoral signs and symptoms are added. A systematic literature analysis yielded 408 entities of which a causal gene has been identified in 79%. We classified dental disorders in eight groups: dental agenesis, supernumerary teeth, dental size and/or shape, enamel, dentin, dental eruption, periodontal and gingival, and tumor‐like anomalies. We aim the classification to act as a shared reference for clinical and epidemiological studies. We welcome critical evaluations of the definitions and classification and will regularly update the classification for newly recognized conditions.     

Polydactyly: phenotypes,genetics and classification

Polydactyly is one of the most common hereditary limb malformations featuring additional digits in hands and/or feet. It constituted the highest proportion among the congenital limb defects in various epidemiological surveys. Polydactyly, primarily presenting as an additional pre‐axial or post‐axial digit of autopod, is a highly heterogeneous condition and depicts broad inter‐ and intra‐familial clinical variability. There is a plethora of polydactyly classification methods reported in the medical literature which approach the heterogeneity in polydactyly in various ways. In this communication, well‐characterized, non‐syndromic polydactylies in humans are reviewed. The cardinal features, phenotypic variability and molecular advances of each type have been presented. Polydactyly at cellular and developmental levels is mainly a failure in the control of digit number. Interestingly, GLI3 and SHH (ZRS/SHH enhancer), two antagonistic factors known to modulate digit number and identity during development, have also been implicated in polydactyly. Mutations in GLI3 and ZRS/SHH cause overlapping polydactyly phenotypes highlighting shared molecular cascades in the etiology of additional digits, and thus suggesting the lumping of at least six distinct polydactyly entities. However, owing to the extreme phenotypic and clinical heterogeneity witnessed in polydactyly a substantial genetic heterogeneity is expected across different populations and ethnic groups.     

Non‐syndromic anophthalmia/microphthalmia can be caused by a PORCN variant inherited in X‐linked recessive manner

Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations, corresponding, respectively, to absent eyeball or reduced size of the eye. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome. Genetic heterogeneity has been demonstrated, and many genes have been reported to be associated with A/M. The advances in high‐throughput sequencing have proven highly effective in defining the molecular basis of A/M. Nevertheless, there are still many patients with unsolved genetic background of the disease, who pose a significant challenge in the molecular diagnostics of A/M. Here we describe a family, with three males affected with the non‐syndromic A/M. Whole exome‐sequencing performed in Patient 1, revealed the presence of a novel probably pathogenic variant c.734A>G, (p.[Tyr245Cys]) in the PORCN gene. Pedigree analysis and segregation of the identified variant in the family confirmed the X‐linked recessive pattern of inheritance. This is the first report of X‐linked recessive non‐syndromic A/M. Until now, pathogenic variants in the PORCN gene have been identified in the patients with Goltz syndrome, but they were inherited in X‐linked dominant mode. The ocular phenotype is the only finding observed in the patients, which allows to exclude the diagnosis of Goltz syndrome.     

Kernels vs. Ears,and Other Questions for a Science of Treatment Dissemination

[Clin Psychol Sci Prac 18: 41–46, 2011] Combining intervention diffusion with change in clinical practice and public policy is an ambitious agenda. The impressive effort in Hawaii can be instructive, highlighting questions for a science of treatment dissemination. Among these questions, some of the most important are the following: (a) Who should be targeted for change? (e.g., “downstream” clinicians in practice, “upstream” clinicians in training, consumers, “brokers,” policy makers, or payers?); (b) What should be disseminated? (e.g., full evidence‐based protocols, specific treatment elements or “kernels”?); and (c) Which procedures maximize change? (e.g., what combination and duration of teaching, supervision, consultation, and other support?). Ultimately, change efforts need to assess what aspects of practice were actually altered, what measurable impact the changes had on clinical outcomes, and what changes in practices and outcomes can be sustained over time.     

IRF6 mutation screening in non‐syndromic orofacial clefting: analysis of 1521 families

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non‐syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non‐syndromic OFCs. Screening for IRF6 mutations in apparently non‐syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non‐syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non‐syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24–0.44% of apparently non‐syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.     

Ectodermal dysplasias: not only 'skin' deep

The ectodermal dysplasias (EDs) are a large and complex nosologic group of diseases; more than 170 different pathologic clinical conditions have been identified. Despite the great number of EDs described so far, few causative genes have been identified. We review EDs in the light of the most recent molecular findings and propose a new classification of EDs integrating both molecular-genetic data and corresponding clinical findings of related diseases.