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

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.

Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.

We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

Premarital Screening and Genetic Counseling Program: Studies from an Endogamous Population.

BACKGROUND: Studies in Arab countries have shown a significant lack of knowledge of Premarital Screening and Genetic Counseling (PMSGC) Program. PMSGC can identify and modify, through prevention and management, some behavioral, medical, and other health risk factors known to impact pregnancy outcomes. OBJECTIVE: The aim of this study was to explore the knowledge, attitudes, and practice of Qatari's toward the premarital screening program and shedding more light on a complex matter. MATERIALS AND METHODS: A cross-sectional study based on Hospitals and Primary Health Care Centers. A total sample of 1246 participants was surveyed, and 873 participants (70.0%) expressed their consent to participate in the study during January 2013-May 2014. The questionnaire based on sociodemographic data and for responses, on the PMSGC program knowledge, attitude, and practice statements. In addition, questions were asked regarding the services, activities, and how to attract and motivate the PMSGC program. RESULTS: The mean age and standard deviation (SD) of the males' age were 30.4 ± 6.50 and the mean and SD of females' age were 31.08 ± 5.98. There were statistically significant differences between males and females with regard to age, educational status, occupation status, household income, consanguinity, body mass index, cigarette smoking, and Shisha smoking. There were no any statistically significant differences between males and females regarding sickle cell anemia and thalassemia, glucose-6-phosphate dehydrogenase deficiency cystic fibrosis, homocystinuria, HIV, and hepatitis. The response to the ''Why proceeding through high-risk marriage?'' by gender, males and females responded statistically significant differences (P = 0.019). The step-wise multivariate regression analyses as predictors for knowledge of PMSGC program revealed that age, educational level, the lack knowledge of genetics counseling, parental interventions for cousin marriage decision, positive test results affect and change marriage decision, religious impact, household income, consanguinity, hereditary diseases knowledge, occupational status, and love factors were considered as the main factors associated with the premarriage screening and genetics counseling after adjusting for age, gender, and other variables. CONCLUSION: The current study revealed that knowledge and attitude regarding PMSGC program were low in population. Motivation, enforcement, and implementation of program at the school and university educational campaigns are vital. Improved counseling and adding new topics for counseling on genetic, chronic, and mental illness; building healthy families; and reproduction and fertility are considered to be top priorities in community.