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.

Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K-AKT-mTOR signaling pathway.

OBJECTIVES: To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway. METHODS: We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid. RESULTS: During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K-AKT-mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA-related overgrowth spectrum, and in seven fetuses with isolated HMEG. No pathogenic variant was identified in the 11th case with HMEG. Four fetuses with limb overgrowth also had one or more lymphatic malformations (LM) and harbored a postzygotic PIK3CA variant. NGS on cultured amniocytes performed in 10 cases, of which nine had been found positive on analysis of pathological fetal tissue, showed variants in four, in either PIK3CA, PIK3R2 or AKT3. CONCLUSIONS: Isolated MEG or HMEG may lead to identification of genetic variants in the PI3K-AKT-mTOR signaling pathway. Cases of limb overgrowth and LM or isolated HMEG are likely associated with PIK3CA variants. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

[Obstetrical anal sphincter injuries and vacuum-assisted delivery at term in primiparas]. / Lésions obstétricales du sphincter de l'anus et ventouse obstétricale chez des primipares à terme.

OBJECTIVES: Operative Vaginal Delivery (OVD) is subject to a risk of perineal tears especially of Obstetrical Anal Sphincter Injuries (OASIS) that are associated with more complications and impaired quality of life. The main objective of this study was to compare the rate of OASIS in primipara at term with fetus in cephalic presentation depending on the type of delivery: OVD using vacuum extractor and spontaneous delivery. METHODS: This is a single-center retrospective study between 01/01/2010 and 12/31/2014 including all primipara who delivered vaginally at term, a single and living fetus in cephalic presentation. Perineal lesions were classified according to the WHO classification. The primary endpoint was the proportion of OASIS. RESULTS: 3552 patients were included: 2496 spontaneous deliveries (SD) and 1056 OVD (29.72 %). There were twenty sphincter tears (0.56 %): 7 in SD group (0.28 %) and 13 in OVD (1.23 %), P<0.0001, OR=5.10 [2.00; 12.99]. Other risk factors associated with OASIS in univariable analysis were: maternal age (≥30 years), duration of expulsive efforts (≥20min) and a birth weight≥4000g. CONCLUSION: In these patients, the risk of OASIS in case of AI increases by a factor of 5;10. The high rate of AI in these patients exposes them to a real risk of OASIS. However, the proportion of OASIS in this group remains lower than those reported in the literature and is barely higher than the national overall rate, despite a very restrictive policy of the use of episiotomy.