Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations of the VPS33B encoding the vacuolar protein sorting 33B (VPS33B), which is involved in the intracellular protein sorting and vesicular trafficking. We report a rare case of ARC syndrome without arthrogryposis caused by a novel mutation of VPS33B. A female patient of Greek origin presented on the 14 th day of life with renal tubular acidosis, Fanconi syndrome, nephrogenic diabetes insipidus, and cholestasis with normal gamma-glutamyl transpeptidase, without arthrogryposis and dysmorphic features. She was born to apparently healthy, nonconsanguineous parents. Additional features included dry and scaling skin, generalized hypotonia, hypoplastic corpus callosum, neurodevelopmental delay, failure to thrive, short stature, recurrent febrile episodes with and without infections, and gastrointestinal bleeding. DNA testing revealed that the patient was homozygous for the novel c.1098_1099delTG (p.Glu367Alafs∗17) mutation of exon 14 of VPS33B gene (NM_018668) on chromosome 15q26.1, leading to a nonsense frameshift variant of VPS33B with premature termination of translation. Her parents were heterozygous for the same VPS33B mutation. The prognosis was predictably poor in the context of the intractable polyuria necessitating long-term parenteral fluid administration via indwelling central catheter leading to catheter-related sepsis, to which she eventually succumbed at the age of 7 months. This is the first published VPS33B mutation in an ARC patient of Greek origin. The current case adds to the spectrum of ARC-associated VPS33B mutations and provides evidence supporting the existence of incomplete ARC phenotype. Increased awareness and early genetic testing for ARC are suggested in cases with isolated cholestasis and/or renal tubular dysfunction, even in the absence of arthrogryposis.
Clinical findings and pedigree analysis led to the diagnosis of severe Norrie disease in two brothers. DNA sequencing demonstrated a novel missense mutation (703G>T) that significantly alters predicted protein structure. Less severe retinal developmental disease may be associated with milder mutations in the Norrie disease gene. J Pediatr Ophthalmol Strabismus 2004;41:361–363.
A family with two male children affected with ASD and HME as well as an unaffected female child, was studied to identify the Genetic basis of ASD in the family and the possible relation between ASD & HME. Irie et al., [PNAS, 109: 5052–5056, 2012] reported that Heparan Sulfate deficient mice due to inactivating EXT-1 mutations exhibit Autism-like socio-communicative deficits and stereotypies suggesting a relation between MHE and ASD. The father and both male children are clinically affected by HME and carry the known pathogenic EXT-1 c.C1018T/p.R340C dominant mutation. Both male children are also affected by ASD; the father is not. The mother and the female child are not affected either by HME or ASD and do not carry the EXT-1 mutation. Whole-Genome SNP genotyping and CNV analyses did not detect aneuploidy or deletion/duplication defects as possible ASD causes. WGNGS for all members, comparative genome analyses and data mining were as follows: [Only exonic variants considered, prioritized according to increasing population frequency (0–1%), damaging effects according to mutation prediction models and will be presented in table format]. 1. The two ASD events are unrelated and are due to de-novo variants. Trio analyses identified 72 de-novo variants in the first affected child and 56 in the second. Twelve were in common 2. The two ASD events are due to heterozygous variants inherited from both parents which in synergy exceed a disease onset threshold in the affected offspring. Eighty father-to-son and 69 mother-to-son heterozygous variants shared between the affected males were identified. 4. The HME unaffected parent [mother] contributed heterozygous variants in the Heparan Sulfate biosynthesis pathway that in synergy with the EXT-1 mutation could be the genetic causes of ASD in the family. WGNGS and comparative genome analyses were utilized to decipher the possible relationship between HME and ASD in this unique family with members affected by both disorders.
To report a novel KERA mutation associated with autosomal recessive cornea plana in members of a nuclear family and to describe their ophthalmic phenotypes.Ophthalmic examination, biometry, and direct sequencing of KERA.Five of the 6 siblings were affected and had small flat corneas, variable anterior chamber depths, and short axial lengths. The remaining brother and the 2 parents had normal ophthalmic examinations. Genetic testing revealed a novel homozygous nonsense mutation in exon 3 [937C>T] in the clinically affected individuals. The clinically unaffected parents were confirmed as carriers. The clinically unaffected sibling had no KERA mutation. This mutation leads to replacement of an arginine by a stop codon at position 313 of keratocan protein.This novel point mutation in KERA is the fourth thus far described. The ocular phenotype is characteristic of autosomal recessive cornea plana.
Multiple endocrine neoplasia type 2 [MEN 2] is an autosomal dominant cancer syndrome with two subtypes, 2A and 2B. MEN 2A and medullary thyroid cancer [MTC] are caused by > 25 different point mutations in exons 10, 11, and 13 of the RET proto-oncogene, whereas MEN 2B is caused by a single exon 16-point mutation. Various molecular methods have been used to identify the different mutations, including DNA sequencing, restriction enzymatic analyses, chemical cleavage mismatch, Single Stranded Conformational Polymorphism [SSCP], and Denaturing Gradient Gel Electrophoresis [DGGE]. These techniques, although useful and accurate, are labor intensive and some involve the use of radioactivity. We have developed a multiplex PCR assay simultaneously to amplify exons 10, 11, and 13 of the RET proto-oncogene. The multiplex PCR product is then analyzed on a modified Mutation Detection Enhancement [MDE] matrix for heteroduplex identification and visualized with ethidium bromide. Distinct heteroduplexes were detected for each known RET proto-oncogene mutation available in our laboratory (nine in exon 10, five in exon 11, one in exon 13, and the single exon 16 mutation). Presymptomatic DNA diagnosis of MEN 2 is essential since pentagastrin-stimulated calcitonin studies can occasionally produce false positive results and lead to unnecessary thyroidectomies. Prophylactic thyroidectomy is recommended by age 5 or 6 once a mutation is identified in a patient, since penetrance is very high. MDE heteroduplex detection provides a quick, efficient, and inexpensive method of screening for RET mutations in MTC patients with unknown mutations, or for presymptomatic diagnosis in individuals at risk for inheriting a known RET mutation. Confirmation of the specific mutation can be achieved by restriction enzymatic digestion (if feasible) or by DNA sequencing.
Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is an autosomal dominant autoinflammatory disease caused by mutations in the proline-serine-threonine phosphatase-interacting protein 1, PSTPIP1.
The produced protein is a cytoskeleton-associated adaptor protein that modulates T-cell activation, cytoskeletal organization and IL-1β release.
The only two mutations described so far, A230T and E250Q, have been found in patients and families, and are thought to disrupt the binding of PSTPIP1 with PTP-PEST, a regulatory phosphatase, and increase its avidity for pyrin in the cytosol, thereby dysregulating IL-1β production. PAPA syndrome typically presents with recurrent sterile, erosive arthritis in childhood, resulting in significant joint destruction. By puberty, joint problems tend to subside and cutaneous symptoms increase including pathergy, frequently with abscesses at the sites of injections, severe cystic acne, and recurrent non-healing sterile ulcers, often diagnosed as pyoderma gangrenosum.
Homozygous deletion of the p16 tumour suppressor gene (at frequencies ranging from 14% to 29%) have been implicated in the pathogenesis of acute lymphoblastic leukaemia (ALL) by several studies. We investigated the prevalence of this deletion in a group of 46 Arab patients with common ALL. Deletion of p16 was assessed in a multiplex PCR which amplified a 405 bp fragment from exon 2 of the p16 gene, and a 242 bp fragment of the ApoE lipoprotein gene which served as an internal control. Homozygous deletion of p16 in tumour cells could be readily detected in samples containing >75% blasts. Surprisingly, none of the cases in our study showed homozygous deletion of the p16 gene. We also investigated the possibility of other genetic alterations in the p16 gene or mutation in the p21 and CDK4 (not previously reported in ALL) genes which are part of the same signal transduction pathway. A heterozygous G --> A transition at nucleotide position 273 of the p16 gene was present in one patient, but did not result in an amino acid change. A C --> A transversion at codon 88 of the p21 gene, which results in replacement of a phenylalanine with a leucine at position 63, was detected in one patient. In another patient a G --> C transversion in exon 2 at codon 82 (5'-untranslated region of the CDK4 gene) was detected. Results of this study showed mutation of p16, p21 or CDK4 to be rare events in Arab ALL patients.
A consanguineous Qatari family affected by a novel autosomal recessive disorder characterized by severe mental retardation, retinal degeneration, optic nerve atrophy, ataxic gait and edematous puffiness of hands was studied by genome-wide SNP genotyping with Illumina 200K SNP-chips, candidate gene mutation screening and whole exome sequencing for one affected member. Homozygosity mapping indicated a 19.6 MB segment in the long arm of chromosome 4 from 55.8-56.0 Mb. LOD score is calculated for the region of homozygosity to establish linkage. This interval contains more than 100 genes, none of which has been implicated in any of the relevant phenotype. Candidate genes within the region of homozygosity were prioritized by examination of their physiologic roles and possibility of producing the disease phenotype. Screening 30 positional candidate genes showed no pathogenic mutations. Whole exome target enrichment sequencing was performed on ABI SOLiD4 for a single-affected individual. Three non-synonymous variants were positioned within the homozygosity intervals. At the same time a report appeared in the literature describing an Iranian family with very similar clinical characteristics with a defect in the Steroid 5 alpha-Reductase 3 [SRD5A3] gene. This gene localizes within the homozygosity interval and it showed one novel missense variation c.T744G/p.F248L on whole exome sequencing in our Qatari family. The mutation was validated by Sanger sequencing, it co-segregates with the disease phenotype and is not present in the 1000 genome database. The mutation is predicted to be damaging by Polyphen and SIFT protein-modeling software and it is absent in 162 ethnically matched control chromosomes. The protein encoded by this gene is a 318 amino acid enzyme that belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. This protein is necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type I. Biochemical testing reconfirmed a glycosylation defect in the affected individuals. This family presents a unique phenotype in the spectrum of glycosylation defect related disorders.
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