Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG’s list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG’s list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.
Background Autosomal recessive genetic disorders are leading health concerns in countries with consanguineous marriage. However, previously there was no strong association of consanguinity with autosomal dominant or X-linked inheritance patterns. Whether this would be the case in singlet consanguineous families remained unexplored. Methods The current study aimed to identify the disease genes and their inheritance patterns in 12 independent Iranian consanguineous singlet families with syndromic autism. Results Exome sequencing revealed two missense and two nonsense variants (one in each gene: IQSEC2, FOXG1, DMD, and CHKB) in four out of 12 families, thereby offering an aetiologic diagnosis. Autism, intellectual disability, learning disability, developmental delay, and behavioral problems were common features in these four families, and three individuals presented with impaired motor skills such as abnormal gait. Muscular dystrophy coupled with hypotonia were noted in two individuals, whereas in the remaining two families ADHD combined with language/speech delay were present. Along with the two X-linked (IQSEC2 and DMD), one autosomal dominant (FOXG1) and one autosomal recessive genes (CHKB) were found in these four consanguineous families. Two genes-DMD and CHKB- are known to be mainly involved in muscular dystrophy. Limitation: our study significance is limited by the small sample size, 12 individuals, and lack of functional experiment on a VUS on the DMD variant. Conclusion Our findings illustrate the mixed inheritance pattern in consanguineous singlet families and highlight the association of autism spectrum disorder with muscular dystrophy, both of which are seemingly not related.
The most common chronic occupational lung disease is occupational asthma. This study aimed to assess the prevalence of work-related respiratory symptoms (WRS) in asthmatic adults at pulmonary clinics. A cross-sectional study was performed. Current employed subjects were subdivided into 2 groups by WRS status according to questionnaire mainly based on one developed by the National Institute for Occupational Safety and Health (NIOSH). Subjects' occupation and workplace exposures were evaluated by asthma-specific job exposure matrix (JEM). Thirty-nine of 179 current employed asthmatics had WRS. Subjects with WRS were more likely to have self-reported allergy and exposure to low-molecular-weight antigens (prevalence ratio [PR]: 2.7). The 2 most frequent occupational classes for asthmatics with WRS were trades, transport and equipment operators, and processing and manufacturing. Self-reported allergy, high-risk exposures, and occupations unique to processing, manufacturing, and utilities were estimated to be risk factors of WRS.
Objectives This study aimed to evaluate the biochemical factors, genetic mutations, outcome of treatment, and clinical follow-up data of Iranian patients with tetrahydrobiopterin (BH4) deficiency from April/2016 to March/2020. Methods Forty-seven BH4 deficiency patients were included in the study and underwent biochemical and genetic analyses. The clinical outcomes of the patients were evaluated after long-term treatment. Results Out of the 47 (25 females and 22 males) BH4 deficiency patients enrolled in the study, 23 were Dihydropteridine reductase (DHPR) deficient patients, 23 were 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficient patients, and one was GTP-Cyclohydrolase 1 deficiency (GTPCH-1) patient. No clinical symptoms were observed in 10 of the DHPR deficient patients (before and after the treatment). Also, most patients diagnosed at an early age had a proper response to the treatment. However, drug therapy did not improve clinical symptoms in three of the patients diagnosed at the age of over 10 years. Also, 16 PTPS deficiency patients who were detected within 6 months and received treatment no clinical symptoms were presented. One of the patients was detected with GTPCH deficiency. Despite being treated with BH4, this patient suffered from a seizure, movement disorder, mental retardation, speech difficulty, and hypotonia. Conclusions The study results showed that neonatal screening should be carried out in all patients with hyperphenylalaninemia because early diagnosis and treatment can reduce symptoms and prevent neurological impairments. Although the BH4 deficiency outcomes are highly variable, early diagnosis and treatment in the first months of life are crucial for good outcomes.
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