Using exome sequencing to decipher family history in a healthy individual: Comparison of pathogenic and population MTM1 variants

Abstract

BackgroundWhen a family encounters the loss of a child early in life, extensive genetic testing of the affected neonate is sometimes not performed or not possible. However, the increasing availability of genomic sequencing may allow for direct application to families in cases where there is a condition inherited from parental gene(s). When neonatal testing is not possible, it is feasible to perform family testing as long as there is optimal interpretation of the genomic information. Here, we present an example of a healthy adult woman with a history of recurrent male neonatal losses due to severe respiratory distress who presented to Medical Genetics for evaluation. A family history of additional male neonatal loss was present, suggesting a potential inherited genetic etiology.MethodsAlthough there was no DNA available from the neonates, by performing exome sequencing on the healthy adult woman, we found a missense variant in MTM1 as a potential candidate, which was deemed pathogenic based on multiple criteria including past report.ResultsBy performing an analysis of all known MTM1‐disease associated mutations and control population variation, we can also better infer the effects of missense variations on MTM1, as not all variants are truncating. MTM1‐X‐linked myotubular myopathy is a condition that leads to male perinatal respiratory failure and a high risk for early mortality.ConclusionsThe application of genetic testing in the healthy population here highlights the broader utility of genomic sequencing in evaluating unexplained recurrent neonatal loss, especially when genetic testing is not available on the affected neonates.

Structural rationale to understand the effect of disease-associated mutations on Myotubularin

“…R69S (Class-C) is a mutation derived from a male patient alive with 24 hours ventilator support at the time of detection of the mutation, but with severe XLMTM phenotype [9]. This positively charged residue has been implicated in putative PI5P binding of MTM1, leading to oligomerisation [18]. The initial attempt at measurement of the 3-phosphatase activity of R69S and two constructs associated with the coiled-coil region (R564H- a mutation at the dimeric interface and a shorter construct MTM1ΔCC) showed similar or higher activity than WT MTM1 (data not shown).…”

“…Although the disease is fatal in most males in the neonatal or postnatal period, females carrying mutations in MTM1 were thought to be asymptomatic earlier. However, in the last few years, there have been a few studies on female carriers of XLMTM mutation, and late-onset symptoms such as the gradual decline of respiratory function have been observed, raising the possibility of X-linked haploinsufficiency in females [18,19].…”

“…With the advent of clinical genetics and improved exome sequencing data, several mutations from XLMTM have been identified, which map onto MTM1, and a few have been characterised in terms of lipid phosphatase activity, protein-protein interactions and effects on cell endosomal-lysosomal pathway [9,[15][16][17]. Mutations associated with XLMTM have been found to map all over the MTM1 sequence, but most reported are from the GRAM and phosphatase domains [18]. Although the disease is fatal in most males in the neonatal or postnatal period, females carrying mutations in MTM1 were thought to be asymptomatic earlier.…”

“…In this study, a list of XLMTM mutations from patients with varying levels of disease severity [18,[20][21][22][23][24][25][26][27] were curated for in silico and in vitro characterisation. For structural analyses, two models were created-one for the GRAM and phosphatase domains and a dimeric model of the coiled-coil domain.…”

Application of Full Genome Analysis to Diagnose Rare Monogenic Disorders

“…In addition, detection of structural variants by short-read whole genome sequencing requires additional analytical processes that are often not fully implemented in clinical settings. 15,16 Second, genetic diagnosis of rare disorders often entails "experiments of one," where many sequence variants found in the proband must be vetted against current knowledge (gene/variants and genome reference) to decide if variants meet the diagnostic criteria 17 . Our incomplete biological knowledge limits our ability to identify the "causal variant" for any particular patient.…”