A founder RAB27A variant causes Griscelli syndrome type 2 with phenotypic heterogeneity in Qatari families

Abstract

Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism, immunodeficiency, and occasional hematological and neurological involvement. We reviewed and analyzed the medical records of 12 individuals with GS2 from six families belonging to a highly consanguineous Qatari tribe and with a recurrent pathogenic variant in the RAB27A gene (NM_004580.4: c.244C > T, p.Arg82Cys). Detailed demographic, clinical, and molecular data were collected. Cutaneous manifestations were the most common presentation (42%), followed by neurological abnormalities (33%) and immunodeficiency (25%). The most severe manifestation was HLH (33%). Among the 12 patients, three patients (25%) underwent HSCT, and four (33%) died. The cause of death in all four patients was deemed HLH, providing evidence for this complication's fatal nature. Interestingly, two affected patients (16%) were asymptomatic. This report highlights the broad spectrum of clinical presentations of GS2 associated with a founder variant in the RAB27A gene (c.244C > T, p.Arg82Cys). Early suspicion of GS2 among Qatari patients with cutaneous manifestations, neurological findings, immunodeficiency, and HLH would shorten the diagnostic odyssey, guide early and appropriate treatment, and prevent fatal outcomes.

Hemophagocytic Lymphohistiocytosis in Children with Griscelli Syndrome Type 2 : Genetic, Laboratory findings and Treatment

“…When the studies on GS2 are examined, it has drawn our attention that genetic mutations are concentrated in some regions. The c.514_518del mutation in Turkey and Iran (11), (current study) the c.C550T mutation in a study by Singh et al in India, and the c.244C > T mutation in a study involving 6 families in Qatar by Al-Sulaiman et al (12), (13). However, predisposing any founder affect based on the findings and literature knowledge is less likely due to the lack of population specific databases.…”

Association of rare variants in genes of immune regulation with pediatric autoimmune CNS diseases

“…RAG1, one of the genes involved in Severe Combined Immunodeficiency (SCID) [25], is also reported in association with refractory status epilepticus [26] and optic neuropathy [27]. Other associations include AIRE with autoimmune cerebellar degeneration [28]; RAB27A with developmental regression and seizures [29]; RTEL1 with microcephaly, developmental delay, spastic diplegia, and cerebellar dysfunction [30]; STAT1 with CNS aneurysms and inflammatory spinal cord lesions [31]; SMARCAL1 with microcephaly, developmental delays, and neuronal migration disorders [32]. TTC7A with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis, severe microcephaly, refractory epilepsy, developmental delay, and hypomyelinating leukodystrophy [33]; and ZAP70 with silent brain infarcts [34].…”

Neonatal Onset of Hemophagocytic Lymphohistiocytosis Due to Prenatal Varicella-Zoster Infection in a Neonate with Griscelli Syndrome Type 2

“…Another case was also diagnosed with HLH with a prior EBV infection and died at the age of 39 years. 11 In a study in Turkey by Cetinkaya et.al, on 28 patients with HLH, the median age of the study population was 23 (4.3 to 117) months at the time of the diagnosis of HLH. In a study in Egypt, 101 patients with HLH were enrolled and the median age at presentation was 13.1 months.…”