Joint laxity in homozygotes for severe <i>POU1F1</i> mutations

Shamseldin, Hanan E.; Maddirevula, Sateesh; Nabil, Amira; Alfadhil, Saeed A; Tala, Saeed Al; Alkuraya, Fowzan S.

doi:10.1002/ajmg.a.37941

Cited by 2 publications

(1 citation statement)

References 9 publications

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“…Thus, the autozygome provides a unique opportunity to unmask the phenotypic expression of variants that had only been reported as compound heterozygous. 39 For example, we show here that one PARS2 allele that was reported to cause Alpers syndrome when compound heterozygous only causes nonspecific global developmental delay and brain atrophy when homozygous but with no evidence of lactic acidosis or liver involvement when homozygous. With its potential to render many previously reported variants as homozygous, the autozygome can be very powerful in revealing important phenotypic aspects of alleles, which may not be appreciated otherwise.…”

Section: Discussionmentioning

confidence: 62%

Autozygome and high throughput confirmation of disease genes candidacy

Maddirevula

Alzahrani

Al‐Owain

et al. 2019

Genetics in Medicine

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PurposeEstablishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases.MethodsAutozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines.ResultsWe highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders.ConclusionsOur results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

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Section: Discussionmentioning

confidence: 62%