Diagnostic yield of patients with undiagnosed intellectual disability, global developmental delay and multiples congenital anomalies using karyotype, microarray analysis, whole exome sequencing from Central Brazil

Abstract

Intellectual Disability (ID) is a neurodevelopmental disorder that affects approximately 3% of children and adolescents worldwide. It is a heterogeneous and multifactorial clinical condition. Several methodologies have been used to identify the genetic causes of ID and in recent years new generation sequencing techniques, such as exome sequencing, have enabled an increase in the detection of new pathogenic variants and new genes associated with ID. The aim of this study was to evaluate exome sequencing with analysis of the ID gene panel as a tool to increase the diagnostic yield of patients with ID/GDD/MCA in Central Brazil, together with karyotype and CMA tests. A retrospective cohort study was carried out with 369 patients encompassing both sexes. Karyotype analysis was performed for all patients. CMA was performed for patients who did not present structural and or numerical alterations in the karyotype. Cases that were not diagnosed after performing karyotyping and CMA were referred for exome sequencing using a gene panel for ID that included 1,252 genes. The karyotype identified chromosomal alterations in 34.7% (128/369). CMA was performed in 83 patients who had normal karyotype results resulting in a diagnostic yield of 21.7% (18/83). Exome sequencing with analysis of the ID gene panel was performed in 19 trios of families that had negative results with previous methodologies. With the ID gene panel analysis, we identified mutations in 63.1% (12/19) of the cases of which 75% (9/12) were pathogenic variants,8.3% (1/12) likely pathogenic and in 16.7% (2/12) it concerned a Variant of Uncertain Significance. With the three methodologies applied, it was possible to identify the genetic cause of ID in 42.3% (156/369) of the patients. In conclusion, our studies show the different methodologies that can be useful in diagnosing ID/GDD/MCA and that whole exome sequencing followed by gene panel analysis, when combined with clinical and laboratory screening, is an efficient diagnostic strategy.

Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment

“…The considered manuscripts were published between 2015 and 2022, including 17 [ 15 , 24 , 44 , 47 , 49 , 56 , 58 , 61 – 64 , 66 , 67 , 70 , 76 , 78 , 79 ] in USA, 7 in China [ 45 , 46 , 57 , 65 , 69 , 74 , 75 ], 2 in Canada [ 60 , 80 ], 2 in Australia [ 52 , 54 ], 2 in the UK [ 51 , 71 ], and 1 in France [ 50 ], Poland [ 16 ], the Netherlands [ 48 ], Germany [ 72 ], Turkey [ 77 ], Saudi Arabia [ 59 ], Malaysia [ 73 ], Mexico [ 55 ], and Brazil [ 68 ]. Twenty-two papers were retrospective cohort studies [ 15 , 24 , 45 , 47 , 49 – 51 , 55 , 56 , 63 , 64 , 66 – 68 , 70 , 71 , 73 , 75 , 77 – 79 ], fourteen were prospective cohort studies [ 16 , 44 , 46 , 48 , 52 – 54 , 57 , 59 , 60 , 65 , 72 , 74 ], and three were randomized controlled trials (RCT) [ 58 ...…”

“…As for the third domain, reference standard, one studies [ 78 ] resulted in high risk of bias because information about blind assessment were not reported. In the fourth domain, flow and timing, three studies [ 59 , 63 , 68 ] had high risk of bias, as not all patients received the same reference standard and were not included in the final analysis.

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“…Nine studies [ 24 , 56 , 64 , 66 – 68 , 70 , 71 , 73 ] got a high risk of bias in the applicability section, particularly in the patient selection, as there may be issues related to the enrolment of patients. Eleven studies [ 49 , 51 , 56 , 57 , 61 , 64 , 66 , 67 , 74 , 75 , 79 ] got an unclear risk of bias in the applicability section, more specifically in the reference standard as it was not clear if its interpretation could have influenced the diagnostic accuracy estimates.…”

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

“…Although the benefit of establishing a genetic diagnosis is apparent, resources are limited for marginalized groups and in developing countries [ 10 ]. Many developing countries are only starting to adopt CMA as the first-tier evaluation for GDD/ID [ 36 , 45 ]. It is, again, a shared decision-making process for the patient/family and the ordering provider.…”

Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability

“…According to SysNDD (https://sysndd.dbmr.unibe.ch/Entities (accessed on 30 October 2022)), 995 genes have been definitely linked to ARID, though the magnitude of candidate genes greatly exceeds this number [9] and is expected to be around 3000 [8]. This is reflected in a consistently low diagnostic yield of genetic diagnostic for ID, which has not exceeded 50%, at best [10,11]. In addition, an increasing adaption of next-generation sequencing for prenatal diagnosis and stronger evidence for pathogenicity of reported variants are required for accurate risk estimate; it urges the need for investigation of more informative pedigrees and deep phenotyping.…”