Julie Plaisancié

Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia

Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X‐linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED.

Distal 10q monosomy: New evidence for a neurobehavioral condition?

Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Nevertheless, the patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600xa0kb Smallest Region of deletion Overlap (SRO) has been proposed. In this report, we describe four patients with a distal 10q26 deletion, who displayed attention-deficit/hyperactivity disorders (ADHD). One of them had a marked behavioral profile and relatively preserved cognitive functions. Interestingly, the SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal models. This report emphasizes the importance of the behavioral problems as a cardinal feature of the 10q microdeletion syndrome. Haploinsufficiency of CALY could play a crucial role in the development of the behavioral troubles within these patients.

Constitutional chromoanasynthesis: description of a rare chromosomal event in a patient

Structural alterations in chromosomes are a frequent cause of cancers and congenital diseases. Recently, the phenomenon of chromosome crisis, consisting of a set of tens to hundreds of clustered genomic rearrangements, localized in one or a few chromosomes, was described in cancer cells under the term chromothripsis. Better knowledge and recognition of this catastrophic chromosome event has brought to light two distinct entities, chromothripsis and chromoanasynthesis. The complexity of these rearrangements and the original descriptions in tumor cells initially led to the thought that it was an acquired anomaly. In fact, a few patients have been reported with constitutional chromothripsis or chromoanasynthesis. Using microarray we identified a very complex chromosomal rearrangement in a patient who had a cytogenetically visible rearrangement of chromosome 18. The rearrangement contained more than 15 breakpoints localized on a single chromosome. Our patient displayed intellectual disability, behavioral troubles and craniofacial dysmorphism. Interestingly, the succession of duplications and triplications identified in our patient was not clustered on a single chromosomal region but spread over the entire chromosome 18. In the light of this new spectrum of chromosomal rearrangements, this report outlines the main features of these catastrophic events and discusses the underlying mechanism of the complex chromosomal rearrangement identified in our patient, which is strongly evocative of a chromoanasynthesis.

A Distinct Class of Chromoanagenesis Events Characterized by Focal Copy Number Gains.

Chromoanagenesis is the process by which a single catastrophic event creates complex rearrangements confined to a single or a few chromosomes. It is usually characterized by the presence of multiple deletions and/or duplications, as well as by copy neutral rearrangements. In contrast, an array CGH screen of patients with developmental anomalies revealed three patients in which a single chromosome carries from 8 to 11 large copy number gains confined to a single chromosome or chromosomal arm, but the absence of deletions. Subsequent fluorescence in situ hybiridization and massive parallel sequencing revealed the duplicons to be clustered together in distinct locations across the altered chromosomes. Breakpoint junction sequences showed both microhomology and non‐templated insertions of up to 40 bp. Hence, these patients each demonstrate a single altered chromosome of clustered insertional duplications, no deletions, and breakpoint junction sequences showing microhomology and/or non‐templated insertions. These observations are difficult to reconcile with current mechanistic descriptions of chromothripsis and chromoanasynthesis. Therefore, we hypothesize those rearrangements to be of a mechanistically different origin. In addition, we suggest that large untemplated insertional sequences observed at breakpoints are driven by a non‐canonical non‐homologous end joining mechanism.

Confirmation of TENM3 involvement in autosomal recessive colobomatous microphthalmia

Anophthalmia and microphthalmia are the most severe malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball respectively. More than 20 genes have been shown to be mutated in patients with syndromic and non‐syndromic forms of anophthalmia–microphthalmia. In a recent study combining autozygome and exome analysis, a homozygous loss of function mutation in TENM3 (previously named ODZ3) was reported in two siblings with isolated bilateral colobomatous microphthalmia from a consanguineous Saudi family. Herein, we report a third patient (not related to the previously reported family) with bilateral colobomatous microphthalmia and developmental delay in whom genetic studies identified a homozygous TENM3 splicing mutation c.2968‐2A>T (p.Val990Cysfs*13). This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene.

Incomplete penetrance of biallelic ALDH1A3 mutations

The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes.

FOXE3 mutations: genotype-phenotype correlations

Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene‐based therapies.

MSX2 Gene Duplication in a Patient with Eye Development Defects.

Abstract Background: MSX2 mutations are a very rare cause of craniosynostosis. Gain-of-function mutations may lead to the Boston-type craniosynostosis with limb defects and refraction errors, whereas loss-of-function mutations causes primary osseous defects such as enlarged parietal foramina. Materials and Methods: Herein we report the case of a child with bicoronal synostosis and cutaneous syndactylies, who presented iridal and chorioretinal colobomas. Due to the craniofacial features that were prominent in the clinical picture, the genes involved in craniosynostosis were explored. Results: The patient disclosed an intragenic duplication of the entire MSX2 gene whereas no mutation was identified in any major genes known to be involved in craniosynostosis. Conclusion: This is the first report of an eye development defect due to an increase in the MSX2 copy number in a human being. The implication of this gene in eye development has already been shown in several animal models. Indeed, overexpression of the Msx2 gene in a mouse model resulted also in optic nerve aplasia and microphthalmia. This report expands the phenotypic spectrum of the MSX2 mutations impacting early ocular development knowledge.