Title Genome joint analysis in a child at risk for cerebral adrenoleukodystrophy Title (croatian) Združena analiza genoma u djeteta s rizikom obolijevanja od cerebralne adrenoleukodistrofije Author Matea Bagarić Mentor Mario Ćuk (mentor)Committee member Mario Ćuk (predsjednik povjerenstva)Committee member Jurica Vuković (član povjerenstva)Committee member Marija Jelušić (član povjerenstva)Granter University of Zagreb Defense date and country 2024-09-19, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Whole genome sequencing (WGS) and genome joint analysis represent a paradigm shift in genetic diagnostics, offering an unparalleled ability to uncover the molecular basis of disease. These innovative, cutting-edge technologies are hailed as first-line diagnostic tools and are particularly critical for patients who remain undiagnosed following exhaustion of conventional medical approaches. Genome joint analysis serves as a biointelligent solution to pinpoint elusive genetic variants, enabling earlier and more precise intervention. Our patient was enrolled in the CROseq Genome Program after traditional diagnostic methods failed to uncover the underlying cause of disease. Joint analysis detected a novel likely pathogenic variant in the ABCD1 gene in the child. Although he remains in the pre-symptomatic stage, he is currently at the age of highest risk for developing cerebral drenoleukodystrophy (CALD). In the absence of timely intervention, CALD rapidly progresses to total disability, followed by death, shortly after symptom onset. Early diagnosis is therefore of crucial importance, as hematopoietic stem cell transplantation (HSCT) and ex vivo gene therapy can positively alter the disease trajectory and significantly improve patient outcomes when initiated during the pre-symptomatic stage. Establishing the diagnosis during this critical window, however, can be challenging. The biochemical marker, elevated very long-chain fatty acids (VLCFA), is a non-specific finding shared with other disorders of peroxisomal biogenesis. Additionally, the clinical course is complicated by the heterogeneity of clinical manifestations and the potential for cerebral involvement to begin at any age. In this context, genome joint analysis emerges as a powerful tool, enabling the rapid and precise identification of pathogenic ABCD1 variants and thereby guiding the timely implementation of targeted, life-saving therapies. This review, together with the case presentation, aims to provide a comprehensive overview of drenoleukodystrophy and highlight the clinical relevance and actionable therapeutic potential of genome joint analysis. The unpredictable clinical course and rapid deterioration observed in CALD underscores the significance of genome joint analysis in providing a comprehensive genetic profile that facilitates the implementation of personalized care for a rare disease with a narrow therapeutic window.
Abstract (croatian) Cijelogenomsko sekvenciranje (WGS) i združena analiza genoma predstavljaju promjenu paradigme u genetičkoj dijagnostici, nudeći neusporedivu sposobnost otkrivanja molekularne osnove bolesti. Ove inovativne, najsuvremenije tehnologije prepoznate su kao dijagnostički alati prve linije i posebno su ključne za pacijente koji ostanu nedijagnosticirani nakon iscrpljivanja konvencionalnim medicinskim metodama. Združena analiza genoma služi kao biointeligentno rješenje za otkrivanje teško prepoznatljivih genetičkih varijanti, omogućujući ranu i preciznu intervenciju. Naš pacijent je uključen u CROseq Genome Program nakon što tradicionalne dijagnostičke metode nisu uspjele otkriti temeljni uzrok bolesti. Združenom analizom je identificirana novo otkrivena vjerojatno patogena varijanta gena ABCD1 kod djeteta. Iako je i dalje u predsimptomatskom stadiju, trenutno je u dobi s najvećim rizikom za razvoj CALD-a. Bez pravovremene intervencije, CALD brzo napreduje do potpune invalidnosti, praćene smrću, nedugo nakon pojave simptoma. Rana dijagnoza je stoga od presudne važnosti, jer transplantacija hematopoetskih matičnih stanica (HSCT) i genska terapija mogu promijeniti tijek bolesti i značajno poboljšati ishode za pacijente ako se započnu tijekom predsimptomatske faze. Međutim, postavljanje
dijagnoze tijekom ovog ključnog razdoblja može biti izazovno. Biokemijski marker, povišene masne kiseline vrlo dugog lanca (VLCFA), nespecifičan je nalaz koji se može naći i u drugim poremećajima peroksisomalne biogeneze. Osim toga, klinički tijek zakompliciran je heterogenošću kliničke slike i mogućnošću zahvaćanja mozga u bilo kojoj dobi. U ovom kontekstu, združena analiza genoma predstavlja korisno sredstvo koje omogućuje brzu i preciznu identifikaciju patogenih varijanti ABCD1 gena i time omogućuje pravovremenu primjenu ciljanih terapija koje spašavaju život. Cilj je ovoga preglednog članka s prikazom slučaja pružiti sveobuhvatan uvid u adrenoleukodistrofiju i istaknuti kliničku važnost i učinkovitost združene analize genoma. Nepredvidivi klinički tijek s brzim pogoršanjem zdravstvenog stanja kod CALD-a ukazuje na značaj združene analize genoma u pružanju sveobuhvatnog genetskog profila koji olakšava provedbu personalizirane skrbi za rijetku bolest s uskim terapijskim rasponom.
Keywords
genome joint analysis
whole genome sequencing
ABCD1 gene
cerebral adrenoleukodystrophy
Keywords (croatian)
združena analiza genoma
cijelogenomsko sekvenciranje
ABCD1 gen
cerebralna adrenoleukodistrofija
Language english URN:NBN urn:nbn:hr:105:412584 Study programme Title: Medicine (in English language) Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2024-10-17 08:09:18
