Two novel STRA6 mutations in a patient with anophthalmia and diaphragmatic eventration.
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ABSTRACT:
SUBMITTER: West B
PROVIDER: S-EPMC2710449 | biostudies-literature | 2009 Mar
REPOSITORIES: biostudies-literature
Publications
Two novel STRA6 mutations in a patient with anophthalmia and diaphragmatic eventration.
West B B Bove K E KE Slavotinek A M AM
American journal of medical genetics. Part A 20090301 3
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Project description:Microphthalmia, anophthalmia, and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used single nucleotide polymorphism (SNP) homozygosity mapping (HM) and targeted next-generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous microanophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double-nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, including one individual with Matthew-Wood syndrome (MWS; MCOPS9). STRA6 encodes a transmembrane receptor involved in vitamin A uptake, a process essential to eye development and growth. We have shown that the G304K mutant STRA6 protein is mislocalized and has severely reduced vitamin A uptake activity. Furthermore, we reproduced the MCOPCB phenotype in a zebrafish disease model by inhibiting retinoic acid (RA) synthesis, suggesting that diminished RA levels account for the eye malformations in STRA6 p.G304K patients. The current study demonstrates that STRA6 mutations can cause isolated eye malformations in addition to the congenital anomalies observed in MWS.
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Project description:We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group.
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Project description:Diaphragmatic eventration is a rare anomaly. When patients with this condition undergo general anesthesia, anesthetic management should be performed with particular care owing to the risk of diaphragmatic rupture. Such a rupture can be perioperatively diagnosed using multiple tools including lung ultrasonography. This case report describes the anesthetic management of a male infant with osteochondroma in the distal ulna, presenting with diaphragmatic eventration on the right side.
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Project description:BackgroundAsparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published.MethodsWe report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports.ResultsWES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H).ConclusionThis report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders.
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Project description:BackgroundChilaiditi's sign is an incidental radiographic finding, associated with intestinal disposition located between liver and right diaphragm. It is considered as an acquired rather than a congenital condition and the prevalence ranges from 1.18% to 2.4% according to recent adult retrospective studies. The aspects of this rare entity with regards to a 7-month-old male initially misdiagnosed as diaphragmatic hernia is discussed.Case presentationA 4-month-old Caucasian male was misdiagnosed with a congenital diaphragmatic hernia owing to previous hospitalization with complaints of respiratory tract infection. On admission 3 months later, he was free of any signs and symptoms of intestinal obstruction or respiratory distress. Thorax computed tomography revealed Chilaiditi's sign. A diagnostic laparoscopy was regarded necessary to evaluate the anatomical details. The most prominent finding was the lack of muscle fibers and almost transparent appearance of the medial aspect of the partially eventrated right hemidiaphragm. Owing to delicate anatomical presentation, diaphragmatic plication was considered hazardous. The patient is doing well and under follow-up.ConclusionsIt is obvious that Chilaiditi's sign is not always a completely incidental finding of no consequence, and may indicate an underlying congenital diaphragmatic pathology, clearly defined by laparoscopic evaluation in this case.
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Project description:PURPOSE:Anophthalmia and microphthalmia (A/M) are rare congenital ocular malformations presenting with the absence of eye components or small eyes with or without structural abnormalities. A/M can be isolated or syndromic. The stimulated by retinoic acid gene 6 (STRA6) and Sloan-Kettering viral oncogene homolog (SKI) genes are involved in vitamin A metabolism, and are implicated with A/M developmental abnormalities in human and animal studies. Vitamin A metabolism is vital to normal eye development and growth. This study explores the association of these genes in a cohort of subjects with A/M. METHODS:STRA6 and SKI were screened for sequence variants by direct sequencing of genomic DNA samples from 18 affected subjects with A/M. The DNA samples of 4 external, unrelated controls were initially screened. Eighty-nine additional unrelated controls were screened to confirm that any sequence variants found in the affected subject DNA samples were related to the phenotype. Coding regions, intron-exon boundaries, and untranslated regions were sequenced by standard techniques. Derived DNA sequences were compared to known reference sequences from public genomic databases. RESULTS:For STRA6, a novel coding non-synonymous sequence variant was found in one subject, resulting in an amino acid change from glycine to glutamic acid in residue 217. One novel nonsense sequence variant found in the same subject changed the STRA6 amino acid residue 592 from cytosine to thymine resulting in a premature stop codon. For SKI, a known coding non-synonymous sequence variant (rs28384811) was found in 3 subject DNA samples and 11/89 control DNA samples. Four novel coding-synonymous sequence variants were observed in SKI. CONCLUSIONS:The STRA6 sequence variants reported in this study could play a role in the pathogenesis of A/M by structural changes to the STRA6 protein. We can attribute 4% A/M incidence in this cohort to these sequence variants. Although no SKI sequence variants were found in this cohort, SKI should not be ruled out as a candidate gene for A/M due to the small cohort size.
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Project description:Anophthalmia and microphthalmia (A/M) are developmental ocular malformations defined as the complete absence or reduction in size of the eye. A/M is a highly heterogeneous disorder with SOX2 and FOXE3 playing major roles in dominant and recessive pedigrees, respectively; however, the majority of cases lack a genetic etiology. We analyzed 28 probands affected with A/M spectrum (without mutations in SOX2/FOXE3) by whole-exome sequencing. Analysis of 83 known A/M factors identified pathogenic/likely pathogenic variants in PAX6, OTX2 and NDP in three patients. A novel heterozygous likely pathogenic variant in PAX6, c.767T>C, p.(Val256Ala), was identified in two brothers with bilateral microphthalmia, coloboma, primary aphakia, iris hypoplasia, sclerocornea and congenital glaucoma; the unaffected mother appears to be a mosaic carrier. While A/M has been reported as a rare feature, this is the first report of congenital primary aphakia in association with PAX6 and the identified allele represents the first variant in the PAX6 homeodomain to be associated with A/M. A novel pathogenic variant in OTX2, c.651delC, p.(Thr218Hisfs*76), in a patient with syndromic bilateral anophthalmia and a hemizygous pathogenic variant in NDP, c.293 C>T, p.(Pro98Leu), in two brothers with isolated bilateral microphthalmia and sclerocornea were also identified. Pathogenic/likely pathogenic variants were not discovered in the 25 remaining A/M cases. This study underscores the utility of whole-exome sequencing for identification of causative mutations in highly variable ocular phenotypes as well as the extreme genetic heterogeneity of A/M conditions.
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Project description:Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.
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Project description:Introduction and importanceGiant megacolon requiring emergency surgery is rare. Eventration of the diaphragm associated with giant megacolon is also uncommon.Case presentationWe report a 66-year-old male who presented with abdominal distention and progressive dyspnea. After resuscitation following cardiopulmonary arrest, the patient underwent emergent subtotal abdominal colectomy. Eventration of the diaphragm was found postoperatively and his respiratory condition was insufficient to allow liberation. Plication of both diaphragms was performed through left and right thoracotomy via the 8th intercostal space. Postoperatively the patient made a full recovery.Clinical discussionsChronic constipation is a common health condition. A life-threatening condition secondary to chronic constipation is a rarely documented complication. Diaphragmatic eventration that was caused due to chronic megacolon in symptomatic patients requires surgical treatment.ConclusionsWe describe a patient with giant megacolon and diaphragmatic eventration secondary to idiopathic megacolon. The patient underwent subtotal colectomy and diaphragmatic plication and recovered fully.
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