Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome.

Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. Since its first description in 1998, only 15 individuals from 10 families have been reported, carrying homozygous or compound heterozygous frameshift or nonsense variants in YY1AP1. In a patient with cutaneous and bone syndactyly and a hemorrhagic stroke at the age of 16 months, consistent with a clinical diagnosis of GRNG, we performed exome sequencing after negative array-CGH and congenital limb malformation panel results. Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. Genetic counseling led to the identification of additional family members compatible with GRNG. Here, we provide new insights into the phenotypic variability associated with GRNG and highlight the utility of the detection of small copy number variants to identify the molecular causes of heterogeneous malformative genetic disorders.

Incidental findings in a series of 2500 gene panel tests for a genetic predisposition to cancer: Results and impact on patients.

With next generation sequencing, physicians are faced with more complex and uncertain data, particularly incidental findings (IF). Guidelines for the return of IF have been published by learned societies. However, little is known about how patients are affected by these results in a context of oncogenetic testing. Over 4 years, 2500 patients with an indication for genetic testing underwent a gene cancer panel. If an IF was detected, patients were contacted by a physician/genetic counsellor and invited to take part in a semi-structured interview to assess their understanding of the result, the change in medical care, the psychological impact, and the transmission of results to the family. Fourteen patients (0.56%) were delivered an IF in a cancer predisposition gene (RAD51C, PMS2, SDHC, RET, BRCA2, CHEK2, CDKN2A, CDH1, SUFU). Two patients did not collect the results and another two died before the return of results. Within the 10 patients recontacted, most of them reported surprise at the delivery of IF, but not anxiety. The majority felt they had chosen to obtain the result and enough information to understand it. They all initiated the recommended follow-up and did not regret the procedure. Information regarding the IF was transmitted to their offspring but siblings or second-degree relatives were not consistently informed. No major adverse psychological events were found in our experience. IF will be inherent to the development of sequencing, even for restricted gene panels, so it is important to increase our knowledge on the impact of such results in different contexts.

Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. METHODS: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. RESULTS: 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. CONCLUSION: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

[Sudden cardiac death: A better understanting for a better prevention]. / Mort subite de l'adulte : une meilleure compréhension pour une meilleure prévention.

Sudden cardiac death is defined as a natural and unexpected death, in a previous apparently healthy individual. It represents a major public health issue, with up to 50% of the cardiovascular mortality. Using data from the Paris Sudden Death Expertise Centre registry, this article summarises the main cardiovascular abnormalities associated with sudden cardiac death, the different preventives approaches, and provides a systematic diagnostic approach.

Phenotypic variability and diffuse arterial lesions in a family with Loeys-Dietz syndrome type 4.

Syndromic thoracic aortic aneurysm and dissection (TAAD) can suggest Marfan, vascular Ehlers-Danlos or Loeys-Dietz (LDS) syndromes. Several of the TGFß-pathway-related genes predispose to different types of LDS. Heterozygous loss-of-function variations in TGFß2 have been shown to be responsible for a novel form of syndromic TAAD associated with an impairment of the mitral valve and cerebrovascular disease called Loeys-Dietz syndrome type 4 (LDS4). We report the clinical characterization of a LDS4 French family with sudden deaths and diffuse vascular lesions, caused by a frameshift mutation in TGFß2 gene: c.[995del]; p.(Leu332TrpfsTer27). Clinical characteristics include aneurysm of aortic sinus, skeletal and cutaneous features compatible with a syndromic form of TAAD (joint hypermobility, scoliosis, and easy bruises), intracranial aneurysms and rare mitral valve involvement. Iliac aneurysms, systemic medium caliber arteries dissections, and mild developmental delay were present in the family, and have not been described in LDS4. Phenotypic variability was also an important finding, including absence of clinical vascular events at advanced age in one case. Our data expand the phenotype of LDS4: we confirm that TGFß2 mutations are responsible for true LDS syndrome with non-specific features of connective tissue disorders and diffuse vascular lesions. Adapted vascular follow up and prevention has to be proposed for these patients.

Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly.

Pre-axial polydactyly type II (PPDII, MIM #174500), Werner mesomelic syndrome (MIM %188770) and Haas polysyndactyly (MIM #186200) are a group of closely related conditions caused by mutations in a long-range Sonic hedgehog (SHH, MIM *600725) regulator called ZRS. To date, 19 point mutations, 10 duplications and 1 triplication of the ZRS associated with those pre-axial polydactylies have been reported in humans, mice, cats and chickens. Some of these have been shown to cause ectopic expression of Shh in the limb bud in mice, leading to a polydactylous phenotype, but the precise mechanism by which ZRS mutations generate this phenotype remains unknown. We present two PPDII families with fully penetrant point mutations in ultra-conserved predicted binding sites for transcription factors SOX9 and PAX3, two possible candidates for regulating SHH expression. Screening for point mutations or copy-number variation of the ZRS, high-resolution array-CGH, and screening of other conserved non-coding sequences (CNS) surrounding SHH in a third family are negative. This is the sixth PPDII pedigree with possible linkage to 7q36 that presents with no detectable ZRS mutation. We hypothesize that another nearby regulatory sequence, or an undetected position effect between ZRS and SHH, could be responsible for negative familial cases linked to 7q36.

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.

BACKGROUND: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. OBJECTIVES: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. METHODS: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with 90% (M(inactive)) peak I(Na) reduction were analyzed separately. RESULTS: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group. CONCLUSION: In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

Sodium channel blocker tests allow a clear distinction of electrophysiological characteristics and prognosis in patients with a type 2 or 3 Brugada electrocardiogram pattern.

BACKGROUND: Patients with a type 2 or 3 Brugada syndrome (BS) pattern and a negative sodium channel blocker challenge (SCBC) are not considered as affected. Their arrhythmic prognosis is generally considered good, but it has never been specifically evaluated. OBJECTIVE: The purpose of this study was to evaluate the arrhythmic prognosis in patients with a type 2 or 3 electrocardiogram (ECG) not converted to type 1 ECG during an SCBC. METHODS: Clinical data, 12-lead ECG, results of the SCBC and electrophysiological study (EPS), and follow-up were collected. RESULTS: Among the 500 patients who underwent an SCBC in our institution, 158 displayed a type 2 or 3 ECG. After the SCBC, 93 (59%) had a type 1 ECG (positive group [PG]), whereas 65 (41%) remained negative (negative group [NG]). An EPS was performed in 31 (33%) PG patients and 15 (23%) NG patients. Ventricular fibrillation was induced in 21 PG patients (67%), whereas no patient in the NG was inducible (P <.001). During a follow-up of 37 +/- 17 months, no sudden death occurred. Three syncopes were observed in the NG versus one syncope, two ventricular tachycardias, and one appropriate shock in the PG. CONCLUSION: This study demonstrates that the presence or absence of coved type ST-segment elevation during the SCBC denotes a profound electrophysiological difference as demonstrated by the absence of inducibility during EPS in the NG that may be responsible for the good prognosis of patients with a type 2 or 3 ECG pattern not converted to type 1.