Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort.

PURPOSE: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. METHODS: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. RESULTS: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. CONCLUSION: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.

Genomic multidisciplinary teams: A model for navigating genetic mainstreaming and precision medicine.

AIM: Recent rapid advances in genomics are revolutionising patient diagnosis and management of genetic conditions. However, this has led to many challenges in service provision, education and upskilling requirements for non-genetics health-care professionals and remuneration for genomic testing. In Australia, Medicare funding with a Paediatric genomic testing item for patients with intellectual disability or syndromic features has attempted to address this latter issue. The Sydney Children's Hospitals Network - Westmead (SCHN-W) Clinical Genetics Department established Paediatric and Neurology genomic multidisciplinary team (MDT) meetings to address the Medicare-specified requirement for discussion with clinical genetics, and increasing genomic testing advice requests. METHODS: This SCHN-W genomic MDT was evaluated with two implementation science frameworks - the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) and GMIR - Genomic Medicine Integrative Research frameworks. Data from June 2020 to July 2022 were synthesised and evaluated, as well as process mapping of the MDT service. RESULTS: A total of 205 patients were discussed in 34 MDT meetings, facilitating 148 genomic tests, of which 73 were Medicare eligible. This was equivalent to 26% of SCHN-W genetics outpatient activity, and 13% of all Medicare-funded paediatric genomic testing in NSW. 39% of patients received a genetic diagnosis. CONCLUSION: The genomic MDT facilitated increased genomic testing at a tertiary paediatric centre and is an effective model for mainstreaming and facilitating precision medicine. However, significant implementation issues were identified including cost and sustainability, as well as the high level of resourcing that will be required to scale up this approach to other areas of medicine.

Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy.

The sodium-dependent multivitamin transporter encoded by SLC5A6 is responsible for uptake of biotin, pantothenic acid, and α-lipoic acid. Thirteen individuals from eight families are reported with pathogenic biallelic SLC5A6 variants. Phenotype ranges from multisystem metabolic disorder to childhood-onset peripheral motor neuropathy. We report three additional affected individuals with biallelic SLC5A6 variants. In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS) with a paternal NM_021095.4:c.393+2T>C variant and a maternal c.1285A>G p.(Ser429Gly) variant. An uncle with recurrent cytopenia and peripheral neuropathy was subsequently found to have the same genotype. We also report an unrelated female with peripheral neuropathy homozygous for the c.1285A>G p.(Ser429Gly) recurrent variant identified in seven reported cases, including this study. RT-PCR studies on blood mRNA from AII:1 showed c.393+2T>C caused mis-splicing with all canonically spliced transcripts in AII:1 containing the c.1285A>G variant. SLC5A6 mRNA expression in AII:1 fibroblasts was ~50% of control levels, indicative of nonsense-mediated decay of mis-spliced transcripts. Biotin uptake studies on AII:1 fibroblasts, expressing the p.(Ser429Gly) variant, showed an ~90% reduction in uptake compared to controls. Targeted treatment of AII:1 with biotin, pantothenic acid, and lipoic acid resulted in clinical improvement. Health Economic analyses showed implementation of GS as an early investigation could have saved $ AUD 105,988 and shortened diagnostic odyssey and initiation of treatment by up to 7 years.

Intestinal permeability in children with trichuris dysentry syndrome - abstract

The status of the small intestine in 20 children with Trichuris dysentery syndrome was investigated, using a differential sugar absorption test on separate occasions, i.e., before treatment and after recovery during their growth spurt. Results from these tests were compared with results from 20 controls, matched for age , with no history of gastrointestinal disease. The sugar absorption test involved orally administering a moderately hypertonic sugar solution of rhamnose and lactulose after an overnight fast. Urine was collected in the subsequent 5 hours of the test and frozen -20§C until analysis by HPLC. Results were expressed as the ratio of lactulose/rhamnose excreted over this time period, the normal intestinal ratio of which is 0.05 ñ 0.02. All 20 children with the syndrome had significantly elevated, abnormal permeability ratios (0.37 ñ 0.18; p < 0.001). These ratios were seen to decrease in the children upon recovery (0.14 ñ 0.08) with 6 of the 18 children attaining normal ratios. The 20 controls had an intestinal permiability ratio of 0.10 ñ 0.08 with 10 of them having elevated permeability ratios. Healthy individuals excrete 12-14 percent of the rhamnose dose and less than 1 percent of the lactulose dose. All children with the syndrome excreted less than 12 percent of the oral dose of rhamnose while the amount of lactulose excreted was greater than 1 percent of the oral dose in 17 of the 20 subjects. Similarly, the amount of rhamnose excreted in the children upon recovery was less than 12 percent of the oral dose in 16 of 18 cases. For the controls, all children had a percentage of recovery for rhamnose less than 12 percent and a percentage recovery for lactulose less than 1 percent. The monosaccharide rhamnose demonstrates the degree of absorption through the abundant transcellular routes of the aqueous pores in the cell membrane while the disaccharide lactulose reflects the permeability through the fewer intercellular junctional complexes and extrusion zones. The Trichuris dysentery syndrome, previously known to be a colonic disease, appears from this study to be associated with inflammation of the small intestinal epithelium in man (AU)