Friedreich’s Ataxia (FRDA) is the most common hereditary ataxia and is mainly caused by biallelic GAA repeat expansion in the FXN gene. Rare patients carrying FXN point mutations or intragenic deletions are reported. We describe the first FRDA patient with a chromosome 9 segmental Uniparental isoDisomy (UPiD) unmasking a homozygous FXN expansion initially undetected by TP-PCR. The child presented with a progressive proprioceptive ataxia associated with peripheral sensory neuronopathy and severe scoliosis. Whole genome sequencing (WGS) identified a maternal segmental Uniparental Isodisomy (UPiD) encompassing FXN. Short tandem repeats analysis on WGS showed a biallelic FXN expansion. The identification of a deletion in the primer-annealing region of the TP-PCR explained the initial TP-PCR failure. This is the first documented case of FRDA caused by segmental UPiD. This case highlights the complexity of the molecular diagnosis of FRDA, and emphasises the importance of integrating results from various technical diagnostic approaches.

Journal of the European Academy of Dermatology and VenereologyAccepted Articles LETTER TO THE EDITOR Expanding the phenotype of GTF2E2-associated trichothiodystrophy Brian Sperelakis-Beedham, Corresponding Author Brian Sperelakis-Beedham [email protected] orcid.org/0000-0003-2828-460X Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Correspondence Dr. Brian Sperelakis-Beedham, Robert-Debré University Hospital, 48 Bd Sérurier, 75019 Paris, France. Email address: Email: [email protected]Search for more papers by this authorLyse Ruaud, Lyse Ruaud Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorYoann Vial, Yoann Vial orcid.org/0000-0003-1437-0427 Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorMyriam Rachid, Myriam Rachid Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorFaustine Ageorges, Faustine Ageorges Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorLouise Goujon, Louise Goujon Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAlain Verloes, Alain Verloes Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAnne-Claude Tabet, Anne-Claude Tabet Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorEmmanuelle Bourrat, Emmanuelle Bourrat Department of Dermatology, Hôpital Saint Louis, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this authorJonathan Lévy, Jonathan Lévy Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this author Brian Sperelakis-Beedham, Corresponding Author Brian Sperelakis-Beedham [email protected] orcid.org/0000-0003-2828-460X Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Correspondence Dr. Brian Sperelakis-Beedham, Robert-Debré University Hospital, 48 Bd Sérurier, 75019 Paris, France. Email address: Email: [email protected]Search for more papers by this authorLyse Ruaud, Lyse Ruaud Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorYoann Vial, Yoann Vial orcid.org/0000-0003-1437-0427 Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorMyriam Rachid, Myriam Rachid Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorFaustine Ageorges, Faustine Ageorges Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorLouise Goujon, Louise Goujon Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAlain Verloes, Alain Verloes Genetics Department, APHP, Robert-Debré University Hospital, Paris, FranceSearch for more papers by this authorAnne-Claude Tabet, Anne-Claude Tabet Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France Neuroscience Department, Human Genetics and Cognitive Function Unit, Pasteur Institute, Paris, FranceSearch for more papers by this authorEmmanuelle Bourrat, Emmanuelle Bourrat Department of Dermatology, Hôpital Saint Louis, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this authorJonathan Lévy, Jonathan Lévy Genetics Department, APHP, Robert-Debré University Hospital, Paris, France Plateforme SeqOIA, AP-HP, Paris, France These authors contributed equally to this paperSearch for more papers by this author First published: 04 October 2023 https://doi.org/10.1111/jdv.19545 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/jdv.19545. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

ObjectiveWe aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes. MethodsWe retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France. Results40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated. ConclusionThis work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.

Dear Editor, Aquagenic palmoplantar keratoderma (APPK), also known as Aquagenic Wrinkling, is a rare skin disease characterized by transient skin wrinkling with oedema and whitish papules mostly on the palms, rarely on the soles, after water immersion. It is frequently observed in patients with cystic fibrosis (CF) but also occurs sporadically, often in young women. An excess of carriers of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been observed in patients and a mild phenotype such as a CFTRrelated disorder (CFTRRD) could be unmasked. Other genes might be at play, such as the aquaporin 5 (AQP5) gene, involved in nonepidermolytic Bothniantype palmoplantar keratoderma (NEPPK), which is a permanent condition worsened by water immersion. We investigated the involvement of AQP5 in 198 patients with an isolated APPK (86.9% of women, 92% of Caucasian ethnicity), including those from our previously published cohort. Diagnosis was based on clinical examination by a dermatologist, and familial data were collected, along with sweat test results when available (Table 1). All patients gave their written informed consent to the genetic studies and had an indepth CFTR gene study, leading to unmask CF in one and a CFTRRD in 13. Massive parallel sequencing of the AQP5 coding regions led to identify an AQP5 variant in six patients (3.0%), of whom two also carried a heterozygous CFTR variant (Table 1). Five AQP5 variants are clustered in the cytoplasmic Cterminal tail, where variants implicated in NEPPK are absent. These Cterminal variants could correspond to a mild form of NEPPK, mimicking APPK. Indeed, NEPPKcausing variants are located in the extracellular end of the water channel or in extracellular loops; thus, the mechanism for NEPPK seems to be water conductance dysregulation. On the contrary, the Cterminal AQP5 variants found in this study are expected to moderately impact the 3D structure of AQP5 but they could significantly impair the ability of AQP5 to interact with partners, as well as its subcellular trafficking or stability at the membrane (Figure 1). Recent studies revealed that AQP5's Cterminal tail is compulsory for AQP5 to pass protein quality controls. Specific interactions between this region and multiple junctional proteins also suggest an influence on celltocell adhesion regulation. Hence, differences in variant location may cause different pathological processes and explain differences in the PPK phenotype. Epidemiological data also support the role of Cterminal AQP5 variants, which are significantly more frequent in patients with APPK than in a control population taken from the GnomAD database (OR: 10.0, 95% CI 4.1 to 24.4, p < 0.0001). The sixth AQP5 variant found in this study, p.Asn125del, located in the membranespanning domain, could lead to disturb the overall conformation of the extracellular Cloop, which is important for optimizing water transport. An effect on the stability of the tetramer could also be expected, as the extremities of the Cloop interact with each other in the neighbouring monomers. This study eventually raises the hypothesis of a multifactorial aetiology of APPK, given the role of CFTR and AQP5 in fluid homeodynamics. Heterozygous CFTR and AQP5 variants may therefore be risk factors predisposing to APPK. An oligogenic model could account for the absence of family history of APPK in patients carrying inherited AQP5 variants. It compels us to consider AQP5 variants, even frequent ones, as potential risk factors, especially when combined with CFTR variants. Our results prompt searching for permanent PPK, even if discrete, as well as other cases of PPK in the patients' families. Ultimately, our study underlines the interest of genetic exploration of APPK, including AQP5 alongside CFTR, for medical care, genetic counselling of CF and a better understanding of the mechanisms underlying APPK.

Les kératodermies palmoplantaires (KPP) sont un ensemble hétérogène de maladies dermatologiques rares qui se caractérisent par une hyperkératose palmaire et plantaire. Les KPP peuvent être considérées comme acquises ou héréditaires. Les KPP héréditaires (KPPH) peuvent être classées en 3 groupes : 1) les KPPH non syndromiques isolées ; 2) les KPPH non syndromiques complexes associées à d’autres manifestations cutanées focales, à distance des paumes et des plantes avec ou sans atteinte phanérienne et 3) les KPPH syndromiques associées à des manifestations extracutanées. Le développement du séquençage de nouvelle génération a permis d’identifier, au cours des dix dernières années, de nombreux nouveaux gènes et variants impliqués dans les KPPH. Ces travaux ont notamment montré que des affections, apparemment distinctes, étaient causées par des variants d’un même gène, et que des phénotypes apparemment similaires étaient, au contraire, dus à des variants dans des gènes distincts. Cette revue décrit les différentes causes génétiques des kératodermies palmoplantaires héréditaires non syndromiques isolées pour lesquelles les gènes ont pu être identifiés.

Hypophosphatasia (HPP) is a rare inherited disease affecting bone and dental mineralization due to loss-of-function mutations in the ALPL gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). Prenatal benign HPP (PB HPP) is a rare form of HPP characterized by in utero skeletal manifestations that progressively improve during pregnancy but often still leave symptoms after birth. Because the prenatal context limits the diagnostic tools, the main difficulty for clinicians is to distinguish PB HPP from perinatal lethal HPP, the most severe form of HPP. We previously attempted to improve genotype phenotype correlation with the help of a new classification of variants based on functional testing. Among 46 perinatal cases detected in utero or in the neonatal period for whose ALPL variants could be classified, imaging alone was thought to clearly diagnose severe lethal HPP in 35 cases, while in 11 cases, imaging abnormalities could not distinguish between perinatal lethal and BP HPP. We show here that our classification of ALPL variants may improve the ability to distinguish between perinatal lethal and PB HPP in utero.

Palmoplantar keratodermas (PPK) comprise a heterogenous group of acquired and hereditary disorders marked by excessive thickening of the epidermis of palms and soles. Hereditary PPKs can be classified into 3 groups: 1) isolated non-syndromic PPKs; 2) complex non-syndromic PPKs associated with other ectodermal defects; and 3) syndromic PPKs associated with extracutaneous manifestations. All types of inheritance have been observed: autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial. Some of these disorders are restricted to geographic isolates. This review describes the different genetic causes of hereditary syndromic and complex PPKs for which the genes have been identified. The identification of pathogenic variants has consequences in terms of genetic counseling, appropriate medical care and follow-up, especially for PPKs predisposing to hearing loss, cardiomyopathies, benign tumors or carcinomas. In addition, the development of targeted therapies based on pathophysiology of disorders should allow a more effective treatment of these conditions in the near future.