Autozygome and high throughput confirmation of disease genes candidacy

Abstract

Purpose: Establishing 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.

Methods: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines.

Results: We 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.

Conclusions: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Keywords: ACMG guidelines; candidate genes; variant interpretation.

Fig. 1

Representative images of cases with class 1 phenotypes. a Panel of clinical images of the proband with APC-related Cenani–Lenz syndrome showing the classic bony syndactyly with loss of the normal configuration of the phalanges. b Brain magnetic resonance image (MRI) of the proband with pathogenic variant in ACTL6B showing agenesis of corpus callosum and mild ventricular dilatation (2.70 cm). c Typical skeletal findings in the proband with XRCC2-related Fanconi anemia showing hypoplastic thumbs and dysplastic hips. d Brain MRI image showing thin but complete corpus callosum in the proband with GOLGA2 pathogenic variant. e Clinical images of the proband with Steel syndrome (pathogenic variant in COL27A1) showing characteristic facial and skeletal appearance (elongated face with severe scoliosis). f Facial photograph and MRI brain of the proband with pathogenic variant in CENPF showing small head, relatively large ears, epicanthal folds, blue-tinged sclerae, prominent nose, thin upper lip, and small chin. MRI revealed reduced white matter volume and marginal pachygyria. g Brain MRI image showing mild molar tooth sign in the proband with KIAA0556 pathogenic variant. h Facial photographs of proband with FUT8 pathogenic variant showing coarse face with synophrys, hypertelorism, sparse eye-lashes, low set ears, thick inverted V-shaped lips.

Fig. 2

Representative images of cases with class 2 and 3 phenotypes. a Clinical images of the proband with TXNRD2 pathogenic variant showing dysmorphic facies and a large umbilical hernia. b The two siblings with SCLT1 pathogenic variant showing absence of the anterior lobe of pituitary gland with the evidence of ectopia of the posterior pituitary gland and thalamic hamartoma. c Three families are with CDK9-related CHARGE-like phenotype showing cerebellar atrophy, unilateral choanal atresia, and dysplastic atrophic kidney. d Brain magnetic resonance image (MRI) of proband with pathogenic variant in PARS2 showing severe cerebral volume loss indicating severe brain atrophy, thinning of the corpus callosum, and severe cerebral volume loss in the supratentorial and infratentorial area. e Clinical images of the proband with PLOD3 pathogenic variant showing dysmorphic facies (prominent forehead, short and flat nose, ptosis with compensatory arching of eyebrows, posteriorly rotated low set ears) and hand contractures. f Facial features and MRI images of proband with DMXL2 pathogenic variant represent long face, high forehead, short philtrum, low set ears, and moderate degree of cerebral and brainstem atrophy. g Brain MRI image showing small atrophic cerebellum with prominence of the posterior fossa cerebrospinal fluid (CSF) spaces in the proband with GEMIN4 pathogenic variant. h Facial pictures of index (16DG0071) subject with ABCA2 showing apparent lack of gross dysmorphism.