Atypical Retinal Phenotype in a Patient With Alström Syndrome and Biallelic Novel Pathogenic Variants in ALMS1, Including a de novo Variation

Alström syndrome (ALMS) is a rare autosomal recessive multi-organ syndrome considered to date as a ciliopathy and caused by variations in ALMS1. Phenotypic variability is well-documented, particularly for the systemic disease manifestations; however, early-onset progressive retinal degeneration affecting both cones and rods (cone-rod type) is universal, leading to blindness by the teenage years. Other features include cardiomyopathy, kidney dysfunction, sensorineural deafness, and childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus. Here, we present an unusual and delayed retinal dystrophy phenotype associated with ALMS in a 14-year-old female, with affected cone function and surprising complete preservation of rod function on serial electroretinograms (ERGs). High-throughput sequencing of the affected proband revealed compound heterozygosity with two novel nonsense variations in the ALMS1 gene, including one variant of de novo inheritance, an unusual finding in autosomal recessive diseases. To confirm the diagnosis in the context of an unusually mild phenotype and identification of novel variations, we demonstrated the biallelic status of the compound heterozygous variations (c.[286C > T];[1211C > G], p.[(Gln96*)];[(Ser404*)]). This unique case extends our knowledge of the phenotypic variability and the pathogenic variation spectrum in ALMS patients

Mécanismes rares autour du mode de transmission autosomique récessif : exemples des ciliopathies

Médecine. Génétique médicaleLes ciliopathies sont des maladies génétiques rares dont le mode de transmission est principalement autosomique récessif avec une contribution allélique biparentale. L’étude d’une cohorte strasbourgeoise de 899 patients atteints de ciliopathies a montré l’implication d’une disomie uniparentale (UPD) dans 0,5% à 1% des diagnostics de syndrome de Bardet-Biedl (BBS) selon que la ségrégation familiale ait été faite ou non et, de la même façon, dans 2% à 3% des diagnostics de syndrome d’Alström (AS). Les variants de novo représentent 0,5% à 1% des BBS et 6% à 9% des AS. L’analyse de 10 patients réunionnais atteints de BBS a confirmé un effet fondateur dans le gène ARL6/BBS3. Cette étude a ainsi montré une prévalence non négligeable d’évènements génétiques considérés comme exceptionnels. La présence d’une UPD ou d’un variant de novo permet de préciser le conseil génétique et la démonstration d’un effet fondateur a permis une révision de la stratégie diagnostique du laboratoire

Lessons from two series by physicians and caregivers' self‐reported data in DDX3X ‐related disorders

International audienceAbstract Introduction and Methods We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. Results These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words. Discussion Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention‐deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention‐deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated