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    Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
    (2024)
    POLI HARLOWE, MARIA CECILIA BERTA  
    ;
    Boris Rebolledo-Jaramillo  
    ;
    Víctor Faundes
    ;
    Catalina Lagos
    ;
    Joan Orellana
    <jats:title>Abstract</jats:title><jats:p>Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.</jats:p>
    Scopus© Citations 13  6
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    Silver-Russell syndrome-like features in a child with recombinant chromosome 11 derived from maternal pericentric inversion
    (2024)
    Abraham Urzua
    ;
    Sofía Catena
    ;
    Paulina Morales
    ;
    Guillermo Lay-Son
    <jats:p>Silver-Russell syndrome (SRS) is a well-known syndrome but with heterogeneous etiologies. We present the case of a child with severe SRS-like features resulting from a complex rearrangement of chromosome 11 inherited from his mother. We studied the index case with karyotyping, MS-MLPA and molecular karyotyping. The mother was studied with karyotyping and subtelomeric FISH. We found a child with marked developmental delay and fatal outcome due to failure to thrive, carrying an 11p15 duplication and an 11q25 deletion of maternal origin. We discovered that the mother was a carrier of a pericentric inversion of chromosome 11, with a history of recurrence in other family members who had severe growth retardation and early death. To our knowledge, no similar SRS-like cases have been described in the literature. This report supports the importance of identification the causative genetic mechanism in SRS-like individuals with duplication in 11p15 region due to high risk of recurrence and to provide an appropriate genetic counseling to the family.</jats:p>
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    Palate abnormalities in Chilean patients with chromosome 22q11 microdeletion syndrome
    (2012)
    Guillermo Lay-Son
    ;
    Mirta Palomares
    ;
    M. Luisa Guzman
    ;
    Marcos Vasquez
    ;
    Alonso Puga
      2Scopus© Citations 10
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    Scopus© Citations 20  1
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    Growth in Chilean infants with chromosome 22q11 microdeletion syndrome
    (2012)
    Maria Luisa Guzman
    ;
    DELGADO BECERRA, OROZIMBA IRIS  
    ;
    Guillermo Lay-Son
    ;
    Edward Willans
    ;
    Alonso Puga
      3Scopus© Citations 9
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    Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice
    (2022)
    Dianalee McKnight
    ;
    Ana Morales
    ;
    Kathryn E. Hatchell
    ;
    Sara L. Bristow
    ;
    Joshua L. Bonkowsky
    <jats:sec id="ab-noi220068-4"><jats:title>Importance</jats:title><jats:p>It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.</jats:p></jats:sec><jats:sec id="ab-noi220068-5"><jats:title>Objective</jats:title><jats:p>To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.</jats:p></jats:sec><jats:sec id="ab-noi220068-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.</jats:p></jats:sec><jats:sec id="ab-noi220068-7"><jats:title>Exposures</jats:title><jats:p>Genetic test results.</jats:p></jats:sec><jats:sec id="ab-noi220068-8"><jats:title>Main Outcomes and Measures</jats:title><jats:p>Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.</jats:p></jats:sec><jats:sec id="ab-noi220068-9"><jats:title>Results</jats:title><jats:p>Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).</jats:p></jats:sec><jats:sec id="ab-noi220068-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.</jats:p></jats:sec>
      3Scopus© Citations 70
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      1Scopus© Citations 58  1
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      29  1Scopus© Citations 27