Florence Jobic

Pediatric cardiomyopathies (CM) are rare and heterogeneous heart disorders, including hypertrophic, dilated, restrictive, arrhythmogenic, and non‐dilated CM. While their genetic basis is well characterized in adults, it remains less clearly defined in children particularly in early‐onset apparently isolated and syndromic forms. We conducted a retrospective study (2018–2024) of 59 pediatric patients who underwent Whole‐Exome Sequencing (WES) for CM at Amiens and Lille University Hospitals, aiming to characterize the genetic architecture of pediatric CM. WES identified at least one Variant Of Interest (VOI) in 62.7% of patients (37/59), including 45.8% (27/59) of P/LP variants, and 16.9% (10/59) of VUS. VOI identification yields for HCM and DCM were respectively 67.7% and 57.1%. Yield was higher in patients diagnosed before 1 year of age compared with those diagnosed later (72.7% vs. 56.7%). Variants were identified in classical CM genes, including sarcomeric genes, but also in less typical and syndromic genes. Among patients diagnosed before 6 months, 55% carried a variant in genes associated with syndromic cardiomyopathy, including cases with initially isolated cardiac phenotypes. These findings support the use of WES as a first‐line approach in pediatric CM and highlight the contribution of complex and syndromic genetic architectures to early‐onset and severe diseases.

Congenital heart defects (CHD) are among the most frequent congenital anomalies and represent a significant source of morbidity and mortality in infants. Both genetic and environmental factors are involved, and variants in the MYH6 are potential major genetic factors. The objective of the present study was to describe cardiac phenotypes in individuals with CHD and MYH6 variants. We included individuals with CHD and a MYH6 variant identified in four French genetics laboratories. Clinical and family data were collected. Of the 29 individuals included, 20 (68.9%) had a principal phenotype of left heart defect: hypoplastic left heart syndrome (n = 11, 37.9%), left heart obstruction at multiple sites (n = 6, 20.7%), and coarctation of aorta (n = 3, 10.3%). Nine individuals (31%) had other CHD, such as tetralogy of Fallot, pulmonary stenosis, and septal defects. Prevalence of persistent left superior vena cava (LSVC) was much higher here (n = 11, 37.9%) than in literature (0.31–5.9%). Most of the 19 MYH6 variants were heterozygous, missenses, and inherited. Family screening demonstrated incomplete penetrance and variable phenotypic expressivity. MYH6 variants are associated with various CHD with a predominance of left heart defects and persistent LSVC. Our findings support broad indication for the molecular screening of MYH6 in CHD—particularly when familial recurrence is uncertain.

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.

Variants in RNU4-2 , encoding the small nuclear RNA (snRNA) U4, were recently identified as a major cause of neurodevelopmental disorders (ReNU syndrome). Here, we investigated de novo variants in 50 snRNAs in a French cohort of 23,649 individuals with rare disorders and collected data of additional patients through an international collaboration. Altogether, we identified 133 probands with pathogenic or likely pathogenic variants in RNU4-2 and 15 individuals with de novo and/or recurrent variants in constrained regions of RNU5B-1 , one of five genes encoding U5. These variants cluster in evolutionarily conserved regions of U4 and U5 essential for splicing. RNU4-2 variants affecting stem III are associated with milder phenotypes than those in the T-loop (quasi-pseudoknot). Phaseable variants associated with severe phenotypes occurred on the maternal allele. Individuals with RNU4-2 variants show specific defects in alternative 5’ splice site usage, correlating with variant location and clinical severity. Additionally, we report an episignature associated with severe ReNU syndrome. This study further highlights the importance of de novo variants in snRNAs and establishes RNU5B-1 as a new neurodevelopmental disorder gene.

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.

Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A>G, one large deletion encompassing exon 9 and 10, and a silent change c.750A>G. Transcript analysis performed on patients’ lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A>G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A>G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis.

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.