Case Report: A Deletion Variant in the DCAF17 Gene Underlying Woodhouse-Sakati Syndrome in a Chinese Consanguineous Family.
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ABSTRACT:
SUBMITTER: Chen G
PROVIDER: S-EPMC8498701 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Woodhouse-Sakati syndrome (WSS) (OMIM#241080) is a rare multi-system autosomal recessive disease with homozygous mutation of the DCAF17 gene. The main features of WSS include diabetes, hypogonadism, alopecia, deafness, intellectual disability and progressive extrapyramidal syndrome. We identified a WSS family with a novel DCAF17 gene mutation type in China. Two unconsanguineous siblings from the Chinese Han family exhibiting signs and symptoms of Woodhouse-Sakati syndrome were presented for evaluation. Whole-exome sequencing revealed a homozygous deletion NM_025000.4:c.1488_1489delAG in the DCAF17 gene, which resulted in a frameshift mutation that led to stop codon formation. We found that the two patients exhibited low insulin and C-peptide release after glucose stimulation by insulin and C-peptide release tests. These findings indicate that the DCAF17 gene mutation may cause pancreatic β cell functional impairment and contribute to the development of diabetes.
| S-EPMC8734028 | biostudies-literature
Project description:BackgroundWoodhouse-Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild-to-moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene.MethodHere, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse-Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole-exome sequencing was carried out.ResultAnalysis of the exome data identified a splicing-site deletion NM_025000.3:c.1423-1_1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co-segregation of the variant with the disease phenotypes in the family.ConclusionThe variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse-Sakati syndrome in affected members of the family.
| S-EPMC8761431 | biostudies-literature
Project description:Woodhouse-Sakati syndrome (WSS) is an infrequent autosomal recessive condition characterized by progressive extrapyramidal signs, mental retardation, hypogonadism, alopecia, and diabetes mellitus. This syndrome belongs to a heterogeneous group of inherited neurodegenerative disorders characterized iron accumulation in the brain, and it is caused by mutations of the C2orf37 gene. We report the first Tunisian family with two affected sisters presenting with a phenotype suggestive of WSS. We examined the index patient presenting with movement disorders and mental retardation and then searched for similar cases in her family, which identified a sister with similar signs. We performed a genetic study that confirmed the diagnosis and revealed a c.436delC mutation of the C2orf37 gene. Therefore, WSS is an important consideration in patients presenting with movement disorders and intellectual disability. A high consanguinity contributes to the clustering of such rare autosomal recessive syndromes.
| S-EPMC4886203 | biostudies-other
Project description:Background and purposeWoodhouse-Sakati syndrome is a rare autosomal recessive disorder characterized by hypogonadism, alopecia, diabetes mellitus, and progressive extrapyramidal signs. The disease is caused by biallelic pathogenic variants in the DCAF17 gene. The purpose of this study was to describe the spectrum of brain MR imaging abnormalities in Woodhouse-Sakati syndrome.Materials and methodsWe reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome (12 males, 14 females; age range, 16-45 years; mean age, 26.6 years). Follow-up studies were conducted for 6 patients.ResultsAll patients had abnormal MR imaging findings. The most common abnormalities were a small pituitary gland (76.9%), pronounced basal ganglia iron deposition (73%), and white matter lesions in 69.2%. White matter lesions showed frontoparietal and periventricular predominance. All white matter lesions spared subcortical U-fibers and were nonenhanced. Prominent perivascular spaces (15.3%) and restricted diffusion in the splenium of the corpus callosum (7.6%) were less frequent findings. Follow-up studies showed expansion of white matter lesions with iron deposition further involving the red nucleus and substantia nigra. Older age was associated with a more severe degree of white matter lesions (P < .001).ConclusionsSmall pituitary gland, accentuated iron deposition in the globus pallidus, and nonenhancing frontoparietal/periventricular white matter lesions were the most noted abnormalities seen in our cohort. The pattern and extent of these findings were observed to correlate with older age, reflecting a possible progressive myelin destruction and/or axonal loss. The presence of pituitary hypoplasia and white matter lesions can further distinguish Woodhouse-Sakati syndrome from other neurodegenerative diseases with brain iron accumulation subtypes.
| S-EPMC7655421 | biostudies-literature
Project description:Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1?Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.
| S-EPMC4664784 | biostudies-literature
Project description:Sanjad-Sakati syndrome (SSS) is a rare genetic disorder with autosomal recessive pattern of inheritance characterized by hypoparathyroidism, sever growth failure, mental retardation, susceptibility to chest infection, and dentofacial anomalies. A child with SSS was referred to the dental departmentseeking dental help for sever dental caries which was attributed to his dietary habits and quality of dental tissues. Full restorative rehabilitation was done under general anesthesia. Two years later, the child presented with recurrent caries affecting uncrowned teeth. High carries recurrence rate was blamed for the nutritional habits endorsed by the parents. Only steel crowned teeth survived such hostile oral environment which suggested shifting of treatment strategy towards full coverage restorations instead of classical cavity preparations and fillings during a second attempt for dental treatment under general anesthesia and for the dental treatment of two cousins of the same child. The author recommends effective health education for parents including the nature of their child's genetic disorder, nutritional needs, and dental health education to improve the life style of such children.
| S-EPMC3600134 | biostudies-literature
Project description:Background Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. Case presentation Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G?>?T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. Conclusions The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD. Supplementary Information The online version contains supplementary material available at 10.1186/s12883-021-02134-7.
| S-EPMC7941924 | biostudies-literature
Project description:BACKGROUND:L-2-hydroxyglutaric aciduria (L2HGA) is a progressive neurometabolic disease of brain caused by mutations of in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Cardinal clinical features include cerebellar ataxia, epilepsy, neurodevelopmental delay, intellectual disability, and other clinical neurological deficits. CASE PRESENTATION:We describe an index case of the family presented with generalised tonic-clonic seizure, developmental delay, intellectual disability, and ataxia. Initially, the differential diagnosis was difficult to be established and a SNP genome wide scan identified the candidate region on chromosome 14q22.1. DNA sequencing showed a novel homozygous mutation in the candidate gene L2HGDH (NM_024884.2: c.178G > A; p.Gly60Arg). The mutation p.Gly60Arg lies in the highly conserved FAD/NAD(P)-binding domain of this mitochondrial enzyme, predicted to disturb enzymatic function. CONCLUSIONS:The combination of homozygosity mapping and DNA sequencing identified a novel mutation in Pakistani family with variable clinical features. This is second report of a mutation in L2HGDH gene from Pakistan and the largest family with L2HGA reported to date.
| S-EPMC5819255 | biostudies-literature
Project description:Sanjad-Sakati syndrome (SSS; Online Mendelian Inheritance in Man [OMIM] #241410), also known as hypoparathyroidism-retardation-dysmorphism (HRD) syndrome, is an autosomal recessive disorder in which prenatal-onset extreme growth retardation, congenital hypoparathyroidism and craniofacial dysmorphism result from mutations in the tubulin-specific chaperone E (TBCE) gene on chromosome 1q42-43. We report unique ophthalmic findings in a two-year-old child with molecularly confirmed SSS, who was admitted to Sultan Qaboos University Hospital in Oman at 11 weeks old with bilateral congenital corneal clouding. The ophthalmic findings in this patient were linked to faulty microtubule assembly in the brain, abnormal intracellular membrane transport and the resulting metabolic derangement seen in patients with SSS.
| S-EPMC4117669 | biostudies-literature
Project description:Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome [also known as Woodhouse-Sakati syndrome (WSS)] is a rare autosomal recessive neuroendocrine and ectodermal disorder. The syndrome was first described by Woodhouse and Sakati in 1983, and 47 patients from 23 families have been reported so far. We report on an additional seven patients (four males and three females) from two highly consanguineous Arab families from Qatar, presenting with a milder phenotype of WSS. These patients show the spectrum of clinical features previously found in WSS, but lack evidence of diabetes mellitus and extrapyramidal symptoms. These two new families further illustrate the natural course and the interfamilial phenotypic variability of WSS that may lead to challenges in making the diagnosis. In addition, our study suggests that WSS may not be as infrequent in the Arab world as previously thought.
| S-EPMC6905109 | biostudies-literature