1 - Serviço de Genética Médica, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal.
2 - CGPP–Centro de Genética Preditiva e Preventiva, IBMC, i3S, Universidade do Porto, Porto, Portugal.
- 2022 ACMG Annual Clinical Genetics Meeting, reunião internacional, sob forma de poster
Background: Ververi-Brady syndrome (VBS, OMIM #617982) is a rare cause of neurodevelopmental disorder. It is characterized by developmental delay, intellectual disability, speech delay, learning difficulties, behavioral issues, dysmorphic characteristics (prominent nose, smooth philtrum, large ears and thin upper lip), microcephaly, short stature and neurological features. In early childhood, elevation of creatin kinase is noted. VBS results from heterozygous loss-of-function variants in QRICH1 gene. QRICH1 gene controls endoplasmic reticulum (ER) stress, maintains proteostasis and keeps tissue homeostasis. Dysregulated ER stress responses may compromise synapse formation, function and plasticity. Thus, it supports the hypothesis that pathogenic variants in QRICH1 gene are responsible for developmental delay. Loss of tissue homeostasis is also implied in pathological conditions that included inflammatory and metabolic diseases. Additionally, QRICH1 protein is known to directly interact with more than 40 other proteins, therefore a broader phenotypic spectrum can be expected. So far, only 10 cases were reported in the literature and clinical data remains limited. We report a new patient with VBS aiming to contribute to the recognition of this condition.
Case presentation: A 39-year-old male was first referred to our outpatient genetic department at 17-years-old with severe development delay and dysmorphism. He was the first child of non-consanguineous parents with no relevant family history. Unremarkable pregnancy with full-term delivery. Perinatal period complicated with respiratory distress, low birth weight, cleft palate and hypospadias. During infancy, he was diagnosed with bilateral congenital cataracts and cryptorchidism. Additional medical features included short stature and postnatal microcephaly. He underwent numerous surgeries for his congenital cataracts. At our observation, he showed facial dysmorphism, widow’s peak, large ears, prominent nasal bridge with bulbous tip, long and flat philtrum, thin upper lip, retrognathia and bilateral transverse palmar crease. Extensive investigation was performed with normal karyotype, FRAXA, 7-dehydrocholesterol, chromosomal microarray analysis and molecular study of CREBBP gene. A CT scan revealed suggestive findings of dysmorphic cortical ribbon in the sylvian, peri-sylvian and frontal regions. Exome sequencing revealed a heterozygous variant in QRICH1(NM_001320580.1):c.1672-1G>A (r.spl), classified as likely pathogenic. Parental testing is ongoing. Conclusion: Our patient has been through a diagnostic odyssey that culminated with exome sequencing. The identification of a likely pathogenic variant in QRICH1 explains our patient phenotype and supports the VBS diagnose. A major feature of our patient is bilateral congenital cataracts and we propose that given the role of QRICH1 gene in ER stress, a known mechanism associated with cataracts development, this can be a novel feature associated with VBS. Moreover, our patient’s phenotypic characteristics overlaps with previously described features and encompasses additional findings, expanding the clinical spectrum of VBS. In addition, by reporting a novel null variant affecting the splicing for QRICH1 gene we widen the genotypic range of loss-of-function variants associated with VBS. As more patients are identified, a more comprehensive phenotypic VBS spectrum will be recognized and possible genotype-phenotype correlations can be made. From a practical standpoint, it provided an appropriated genetic counselling and a better surveillance to this patient and family.
Palavras Chave: Ververi-Brady syndrome