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Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

ABSTRACT: We describe a case series of five infants (age range: 1-90 days; 4 females and 1 male) who presented to Al Jalila Children's intensive care units (ICU) with complex multisystem disorders. Patients were Emirati, Kenyan, Jordanian, Filipino, or Pakistani. Trio rapid whole genome sequencing (rWGS) was performed on all five patients and their parents within the hospital's genomics facility. Results were returned within ~37 h from blood sample draws and were diagnostic in 3 out of 5 patients. Positive findings were a homozygous pathogenic variant in POMT1 gene causing muscular dystrophydystroglycanopathy, a mosaic tetrasomy of the short arm of chromosome 12 (12p13.33p11.1) causing Pallister-Killian syndrome, and compound heterozygous pathogenic variants in the LIPA gene causing lysosomal acid lipase deficiency and Wolman disease. The rWGS analysis provided fast and precise diagnostic findings in those 3 patients and also aided in devising better management plans for them in the intensive care setting. For example, the 3-month-old infant with pathogenic variants in the LIPA gene is now a candidate for an FDA-approved, potentially lifesaving enzyme replacement therapy (sebelipase alfa). Our case series emphasize the feasibility and utility of rWGS in pediatric intensive care setting, in a diverse population that has long been underserved in genomic services. Significant investments in local healthcare infrastructure are needed, globally, for more equitable access of genomic medicine among vulnerable patients.

SUBMITTER: Halabi N

PROVIDER: S-EPMC9128109 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

Halabi Nour N Ramaswamy Sathishkumar S El Naofal Maha M Taylor Alan A Yaslam Sawsan S Jain Ruchi R Alfalasi Roudha R Shenbagam Shruti S Bitzan Martin M Yavuz Lemis L Abulhoul Hamda H Shankar Shiva S Janjua Dalwinder D Jadhav Devendrasing D Al Maazmi Munira Mahmoud MM Abuhammour Walid W Alsheikh-Ali Alawi A Al Awadhi Mohamed M Al Khayat Abdulla A Abou Tayoun Ahmad N AN

Genome medicine 20220524 1

We describe a case series of five infants (age range: 1-90 days; 4 females and 1 male) who presented to Al Jalila Children's intensive care units (ICU) with complex multisystem disorders. Patients were Emirati, Kenyan, Jordanian, Filipino, or Pakistani. Trio rapid whole genome sequencing (rWGS) was performed on all five patients and their parents within the hospital's genomics facility. Results were returned within ~37 h from blood sample draws and were diagnostic in 3 out of 5 patients. Positiv ...[more]

PMID: 35606784

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Project description:Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests (n = 32, cases) or standard genetic tests alone (n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10-46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11-53%];p = 0.004). Median age at diagnosis (25 days [range 14-90] in cases vs. 130 days [range 37-451] in controls) and median time to diagnosis (13 days [range 1-84] in cases, vs. 107 days [range 21-429] in controls) were significantly less in cases than controls (p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases.

Project description:Genetic disorders are a frequent cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/PICU). In recent years, rapid genome-wide sequencing (exome or whole genome sequencing) has been applied in the NICU/PICU. However, mtDNA sequencing is not routinely available in rapid genetic diagnosis programs, which may fail to diagnose mtDNA mutation-associated diseases. Herein, we explored the clinical utility of rapid exome sequencing combined with mtDNA sequencing in critically ill pediatric patients with suspected genetic disorders. Rapid clinical exome sequencing (CES) was performed as a first-tier test in 40 critically ill pediatric patients (aged from 6 days to 15 years) with suspected genetic conditions. Blood samples were also collected from the parents for trio analysis. Twenty-six patients presented with neuromuscular abnormalities or other systemic abnormalities, suggestive of suspected mitochondrial diseases or the necessity for a differential diagnosis of other diseases, underwent rapid mtDNA sequencing concurrently. A diagnosis was made in 18 patients (45.0%, 18/40); three cases with de novo autosomal dominant variants, ten cases with homozygous or compound heterozygous variants, three cases with hemizygous variants inherited from mother, three cases with heterozygous variants inherited from either parent, and one case with a mtDNA mutation. The 18 patients were diagnosed with metabolic (n = 7), immunodeficiency (n = 4), cardiovascular (n = 2), neuromuscular (n = 2) disorders, and others. Genetic testing reports were generated with a median time of 5 days (range, 3-9 days). Thirteen patients that were diagnosed had an available medical treatment and resulted in a positive outcome. We propose that rapid exome sequencing combined with mitochondrial DNA sequencing should be available to patients with suspected mitochondrial diseases or undefined clinical features necessary for making a differential diagnosis of other diseases.

Dataset Information

Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

Publications

Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

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