Gilles Morin

Proteus syndrome (PS) is a rare disorder (< 1/1000000), marked by progressive overgrowth commonly impacting the skeleton, skin, adipose tissue, and central nervous system. Clinical criteria were established in 2019. PS arises from a somatic activating variation in the AKT1 gene. We report the second case of PS diagnosed prenatally using whole exome sequencing (WES). A 34‐year‐old woman was referred for nonvisualized anterior brain structures and genital anomalies. At 21 weeks of gestation (WG), ultrasonography confirmed brain anomalies, genital anomalies, and macrosomia. Array‐CGH revealed no pathogenic imbalances (arr(X,1‐22)×2). Follow‐up ultrasound (25 WG) and MRI (27 WG) also showed a megalencephaly, leading to WES on amniocytes. The reported mosaic variation in AKT1 was identified. Medical termination of pregnancy occurred at 30 + 1 WG. We present a case of PS confirmed prenatally via WES. To date, six cases of prenatal PS suspicion have been reported, four of which lacked molecular diagnosis. Calculating prenatal clinical scores indicate PS could not be definitively diagnosed without molecular confirmation. Certain features, such as limb malformation and gray matter heterotopia, seem to be significant in prenatal diagnosis. WES, with an average coverage depth of 130X, is valuable for diagnosing suspected PS.

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p‐22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22‐A identified using FISH, MLPA, and/or array‐CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.

Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow-up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next-generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.