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Background: Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the FGD1 gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients., Methods: Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in FGD1 , through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders., Results: This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations., Conclusion: A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of FGD1 variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

We report an index patient with complete insensitivity to pain and a history of painless fractures, joint hypermobility, and behavioral problems. The index patient descends from a family with notable cases among his maternal relatives, including his aunt and his mother's first cousin, both of whom suffer from congenital insensitivity to pain. The patient had normal results for prior genetic testing: fragile-X syndrome testing, chromosomal microarray analysis, and exome sequencing. Optical genome mapping detected a homozygous deletion affecting the noncoding 5' untranslated region (UTR) and the first non-coding exon of the SCN9A gene in all affected family members, compatible with recessive disease transmission. Pathogenic homozygous loss-of-function variants in the SCN9A gene are associated with impaired pain sensation in humans. Optical genome mapping can thus detect pathogenic structural variants in patients without molecular etiology by standard diagnostic procedures and is a more accessible diagnostic tool than short-read or long-read whole-genome sequencing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boughalem, Ciorna-Monferrato, Sloboda, Guegan, Page, Zimmer, Benazra, Kleinfinger, Lohmann, Valduga, Receveur, Martin and Trost.)

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants., (© 2020 Wiley Periodicals LLC.)