Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification.

BACKGROUND: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity. METHODS: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1). RESULTS: PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation. CONCLUSION: PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.

The value of clinical criteria in identifying patients with X-linked Alport syndrome.

BACKGROUND AND OBJECTIVES: Alport syndrome (AS) is a predominantly X-linked hereditary nephritis associated with high-tone, sensorineural deafness and characteristic eye signs. Clinical diagnostic criteria were defined in 1988. Most cases result from mutations in the X-linked collagen gene COL4A5, with mutations in the autosomal genes COL4A3 and COL4A4 on chromosome 2 accounting for the rest. Mutation analysis of COL4A5 with a combination of sequencing and multiplex ligation-dependent probe amplification has been available for several years. The objective of this study was to determine the utility of clinical diagnostic criteria in identifying patients likely to have a COL4A5 mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Clinical information was available on 206 patients whose DNA was received for testing between 1994 and June 2008; predictive tests for a known familial mutation, samples from duplicate family members, and incompletely screened samples were excluded. One hundred and twenty-eight patients (62.1%) had a pathogenic COL4A5 mutation. RESULTS: The mutation detection rate in families fulfilling zero, one, two, three, or four diagnostic criteria was 0%, 18%, 64%, 89%, and 81%, respectively. Sixty-seven percent of patients with COL4A5 mutations meeting only two diagnostic criteria had not had a complete clinical assessment. In two thirds of families meeting four diagnostic criteria without an identified COL4A5 mutation, autosomal inheritance was confirmed or suspected. CONCLUSIONS: The authors recommend COL4A5 analysis in any patient meeting at least two clinical diagnostic criteria. COL4A3 and COL4A4 analysis should be considered if a COL4A5 mutation is not detected and primarily if autosomal inheritance is suspected.

Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.