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Phenotype-genotype spectrum of AAA syndrome from Western India and systematic review of literature.

ABSTRACT: OBJECTIVE:To study genotype-phenotype spectrum of triple A syndrome (TAS). METHODS:Retrospective chart analysis of Indian TAS patients (cohort 1, n?=?8) and review of genotyped TAS cases reported in world literature (cohort 2, n?=?133, 68 publications). RESULTS:Median age at presentation was 4.75 years (range: 4-10) and 5 years (range: 1-42) for cohorts 1 and 2, respectively. Alacrima, adrenal insufficiency (AI), achalasia and neurological dysfunction (ND) were seen in 8/8, 8/8, 7/8 and 4/8 patients in cohort 1, and in 99, 91, 93 and 79% patients in cohort 2, respectively. In both cohorts, alacrima was present since birth while AI and achalasia manifested before ND. Mineralocorticoid deficiency (MC) was uncommon (absent in cohort 1, 12.5% in cohort 2). In cohort 1, splice-site mutation in exon 1 (p.G14Vfs*45) was commonest, followed by a deletion in exon 8 (p.S255Vfs*36). Out of 65 mutations in cohort 2, 14 were recurrent and five exhibited regional clustering. AI was more prevalent, more often a presenting feature, and was diagnosed at younger age in T group (those with truncating mutations) as compared to NT (non-truncating mutations) group. ND was more prevalent, more common a presenting feature, with later age at onset in NT as compared to T group. CONCLUSION:Clinical profile of our patients is similar to that of patients worldwide. Alacrima is the earliest and most consistent finding. MC deficiency is uncommon. Some recurrent mutations show regional clustering. p.G14Vfs*45 and p.S255Vfs*36 account for majority of AAAS mutations in our cohort. Phenotype of T group differs from that of NT group and merits future research.

SUBMITTER: Patt H

PROVIDER: S-EPMC5705786 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Phenotype-genotype spectrum of AAA syndrome from Western India and systematic review of literature.

Patt Hiren H Koehler Katrin K Lodha Sailesh S Jadhav Swati S Yerawar Chaitanya C Huebner Angela A Thakkar Kunal K Arya Sneha S Nair Sandhya S Goroshi Manjunath M Ganesh Hosahithlu H Sarathi Vijaya V Lila Anurag A Bandgar Tushar T Shah Nalini N

Endocrine connections 20171101 8

<h4>Objective</h4>To study genotype-phenotype spectrum of triple A syndrome (TAS).<h4>Methods</h4>Retrospective chart analysis of Indian TAS patients (cohort 1, <i>n</i> = 8) and review of genotyped TAS cases reported in world literature (cohort 2, <i>n</i> = 133, 68 publications).<h4>Results</h4>Median age at presentation was 4.75 years (range: 4-10) and 5 years (range: 1-42) for cohorts 1 and 2, respectively. Alacrima, adrenal insufficiency (AI), achalasia and neurological dysfunction (ND) wer ...[more]

PMID: 29180348

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Project description:BackgroundDe novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.ObjectivesTo delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.MethodsDiagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.ResultsWe report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.ConclusionWe delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

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Phenotype-genotype spectrum of AAA syndrome from Western India and systematic review of literature.

Publications

Phenotype-genotype spectrum of AAA syndrome from Western India and systematic review of literature.

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