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Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis.

ABSTRACT: In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

SUBMITTER: Shingu K

PROVIDER: S-EPMC8563990 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis.

Shingu Keita K Murase Takehiko T Yamamoto Takuma T Abe Yuki Y Shinba Yoriko Y Mitsuma Masahide M Umehara Takahiro T Yamashita Hiromi H Ikematsu Kazuya K

Scientific reports 20211102 1

In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. Fr ...[more]

PMID: 34728707

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Project description:ObjectiveOgival palate (i.e., a narrow and high-arched palate) is usually described in obstructive breath disorder but has been found in infants unexpectedly deceased. We studied the association between ogival palate and sudden unexpected death in infancy (SUDI) on the basis of a computed tomography (CT) evaluation.MethodsWe conducted a monocentric case-control study of children under 2 years of age who died of SUDI, for which a head CT scan and an autopsy were performed between 2011 and 2018. Each case was matched by sex and age (± 30 days) to two controls selected among living children in the same center who benefited from a cranio-encephalic CT scan. Four parameters of the hard palate were measured by CT: height, width, length, and sagittal angle; the height/width ratio was calculated. The presence of an ogival palate was also subjectively evaluated by the radiologists, independently from the measurements. Standardized odds ratios (OR) were calculated using conditional logistic regression models, all expressed for +1 standard deviation (SD).ResultsThirty-two deceased children were matched to 64 living control children. Mean ages were 5.0 and 5.3 months, respectively. Twenty-eight cases were considered to have died as a result of SIDS. The mean heights of the hard palate were significantly higher in the deceased children [4.1 (± 0.7) millimeters (mm)] than in the living children [3.2 (± 0.6) mm], with OR (+1SD) = 4.30 (95% confidence interval [CI], 2.04-9.06, P = 0.0001). The mean widths of the hard palate were 21.0 (± 1.9) mm and 23.2 (± 2.1) mm, respectively, with OR = 0.15 (95% CI, 0.06-0.40, P = 0.0001). The mean sagittal angles were significantly more acute in deceased children [134.5° (± 9.3)] than in living children [142.9° (± 8.1)], with OR = 0.28 (95% CI, 0.14-0.56, P = 0.0003). The mean height/width ratios were 19.8 (± 3.7) and 14.1 (± 3.3), respectively, with OR = 6.10 (95% CI, 2.50-14.9, P = 0.0001). The hard palate was subjectively considered as ogival in 59.4% (19/32) of the cases versus 12.5% (8/64) of the controls.ConclusionRadiological features of the ogival palate were strongly associated with SUDI. This observation still needs to be confirmed and the corresponding clinical features must be identified.

Project description:Background: The incidence of sudden unexpected death in infancy (SUDI), which includes sudden infant death syndrome (SIDS), has declined in developed countries since the 1980s, including the Netherlands. To identify improvement opportunities in SUDI prevention, we monitored the adherence of parents to the prevention advice on infant care habits over the past 20 years, especially in relation to the SUDI incidence over time. Potential changes in parental adherence between the latest surveys are of specific interest, as these indicate where current focus is needed. Methods: Description of the prevalence of infant care factors related to the risk of SUDI, assessed from five Dutch national surveys from 1999 to 2017 among parents of infants under 12 months, and analysis of the potential differences in these prevalences between the two latest surveys in 2010/11 and 2017 with a z-test. Results: Supine sleeping position decreased from the highest prevalence of 92% in 2010/11, to 83% in 2017. Sleep sack use has increased to 55%, the highest prevalence up to now. Avoiding a duvet has remained reasonably stable since 2002/03 and now 95% of parents do not use a duvet. The prevalence of room-sharing, without sharing the bed, increased from 14% in 1999 to the highest prevalence in 2017 (31%). However, also bed-sharing almost doubled from 5.6% in 2010/11 to 10% in 2017. Breastfeeding decreased between 1999 and 2010/11, but increased from 34% in 2010/11 to 42% in 2017. An increased prevalence of mothers who abstained from smoking during pregnancy, as well as both parents not smoking, was observed, although mostly higher educated parents showed this beneficial behavior. Discussion and Conclusion: Much has already been achieved first by decreasing prone sleeping since the 80's, and subsequently promoting supine as the safest sleep position. The decrease in duvet use and smoking, and an increase in breastfeeding have also had impact. Indications of a recent decreased prevalence of the supine sleeping position and higher prevalence of bed-sharing might relate to the slightly increasing SUDI incidence in the Netherlands. Renewed attention for prevention of SUDI and specific advice targeting high-risk groups is needed. Modern, picture driven information via internet is recommended.

Project description:BACKGROUND:Genetic variation in ion channel genes ('channelopathies') are often associated with inherited arrhythmias and sudden death. Genetic testing ('molecular autopsies') of channelopathy genes can be used to assist in determining the likely causes of sudden unexpected death. However, different in silico approaches can yield conflicting pathogenicity predictions and assessing their impact on ion channel function can assist in this regard. METHODS AND RESULTS:We performed genetic testing of cases of sudden expected death in the New York City metropolitan area and found four rare or novel variants in ABCC9, which codes for the regulatory SUR2 subunit of KATP channels. All were missense variants, causing amino acid changes in the protein. Three of the variants (A355S, M941V, and K1379Q) were in cases of infants less than six-months old and one (H1305Y) was in an adult. The predicted pathogenicities of the variants were conflicting. We have introduced these variants into a human SUR2A cDNA, which we coexpressed with the Kir6.2 pore-forming subunit in HEK-293 cells and subjected to patch clamp and biochemical assays. Each of the four variants led to gain-of-function phenotypes. The A355S and M941V variants increased in the overall patch current. The sensitivity of the KATP channels to inhibitory 'cytosolic' ATP was repressed for the M941V, H1305Y and K1379Q variants. None of the variants had any effect on the unitary KATP channel current or the surface expression of KATP channels, as determined with biotinylation assays, suggesting that all of the variants led to an enhanced open state. CONCLUSIONS:All four variants caused a gain-of-function phenotype. Given the expression of SUR2-containing KATP channels in the heart and specialized cardiac conduction, vascular smooth muscle and respiratory neurons, it is conceivable that electrical silencing of these cells may contribute to the vulnerability element, which is a component of the triple risk model of sudden explained death in infants. The gain-of-function phenotype of these ABCC9 variants should be considered when assessing their potential pathogenicity.

Project description:The French "OMIN registry" was established in 2015 to collect nationwide standardised data concerning biological, clinical, environmental and social characteristics of sudden unexpected death in infancy (SUDI) and unexpected death in children aged 1-2 years. A biobank has existed since July 2020 to store biological samples for each case. This article aimed to detail (1) a brief history and the objectives of the registry; (2) a description of the methodology used; (3) the first results of the registry, i.e. the main characteristics of the cases included so far; (4) the process for accessing the data for research projects; and (5) issues regarding weakness and improvement and perspectives offered by the registry. On 31 May 2024, 1975 cases were included in the OMIN registry; on 31 December 2022, 4606 biological samples from 176 cases were collected. For each deceased child, different types of data are registered on an electronic case report form: socio-demographic data, personal and familial medical background, environment and feeding data, clinical data, and biological and imaging results. A strict and continuous quality control process is used to ensure the reliability of the data, in parallel with specific actions to improve the exhaustiveness of the registry. The OMIN registry database is one of the largest and the most complete databases on SUDI, especially in Europe, and the first in the world to associate a standardised biological sample collection with it. Perspectives of research provided by our registry are numerous and could be supported by national and international scientific collaborations.Conclusion This article details the objectives and methods of the French registry of SUDI. It provides initial results relating to the population included in the register and the procedure for accessing the data.What is known• In Western Europe, France is one of the countries with the highest SUDI rate, making it the first cause of death of infants between 28 and 364 days. • The development of epidemiological tools on a national and international scale is essential to advance research into the determinants and risk factors of unexpected death in children under 2 years of age.What is new• The OMIN registry was created in France in 2015 to collect nationwide standardised social, environmental, clinical, and paraclinical data for cases of unexpected death in children aged 0 to 2 years. • To date, the OMIN registry has included 680 data from almost 2000 children unexpectedly deceased, completed by a biocollection since 2020. • Data from the OMIN registry, unique in its field, are freely available for scientific research teams, after acceptation by the scientific committee of the registry.

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Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis.

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Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis.

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