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Published in final edited form as: Am J Med Genet A. 2024 Jul 19;194(12):e63817. doi: 10.1002/ajmg.a.63817

Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes

Tomoki T Nomakuchi 1, Eden Y Teferedegn 1, Dong Li 1, Kayla J Muirhead 2, Holly Dubbs 2, Jacqueline Leonard 1, Colleen Muraresku 1, Emily Sergio 2, Kaley Arnold 2, Amy Pizzino 2, Cara M Skraban 1,3, Elaine H Zackai 1,3, Kai Wang 1, Rebecca D Ganetzky 1,3, Adeline L Vanderver 4, Rebecca C Ahrens-Nicklas 1,3, Elizabeth J K Bhoj 1,3
PMCID: PMC11540733  NIHMSID: NIHMS2015003  PMID: 39031459

Abstract

Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and noncoding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7–1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.

Keywords: exome sequencing, genome sequencing, neurodevelopmental disability, neurodevelopmental disorders

1 |. INTRODUCTION

Pediatric patients presenting with neurodevelopmental disability (NDD), including those with intellectual disability and epileptic encephalopathy, pose a significant diagnostic challenge. The differential diagnosis considered when evaluating children with NDD is broad, including genetic, metabolic, infectious, inflammatory, endocrine and nutritional etiologies (De Felice et al., 2015; Heland et al., 2022; Jiang et al., 2018; Yu, 2014). As such, these individuals are often subjected to a resource-intensive diagnostic course including comprehensive neuroimaging, metabolic screening, and genetic testing (Thevenon et al., 2016).

Timely and accurate diagnosis of the cause of NDD could have a profound impact on the management and outcome, and several diagnoses are amenable to well-established targeted treatments (Mishra & Mishra, 2018). In addition, advances in other therapeutic modalities such as gene therapy, enzyme replacement therapy and immunotherapy are promising, although genetic confirmation of the diagnoses and a comprehensive understanding of the disease pathogenesis are prerequisite for their ongoing development (Martier & Konstantinova, 2020; Mortada et al., 2021). Unfortunately, a conclusive molecular diagnosis is achieved in a minority of children with NDD with suspected underlying genetic etiology (Srivastava et al., 2019).

Exome sequencing (ES) has emerged as an indispensable tool in the diagnostic investigation of individuals with undiagnosed NDD, and achieves a diagnostic rate of approximately 30% (Carter et al., 2023; Thevenon et al., 2016). Although ES is regarded as a comprehensive genetic test with accordingly high diagnostic yield, rare Mendelian diagnoses can be missed on ES due to several technical limitations. These limitations include poor coverage of non-coding regions, coverage depth variation due to biased capture and amplification, and poor sensitivity for copy number variants (CNVs) and structural variants (Burdick et al., 2020; Meienberg et al., 2016). Modern ES platforms addresses some of these challenges with improved analysis pipelines and capture kits (Corominas et al., 2022). CNV in particular are reliably detected in modern ES platform, in comparison to older ES platforms that were not clinically validated to report CNVs (Testard et al., 2022).

Genome sequencing (GS) addresses many of the technical limitations of ES. In addition to providing coverage of non-coding regions, it also improves sensitivity for structural and repeat number variants due to uniform coverage depth across the genome (Bertoli-Avella et al., 2021; Mattick et al., 2018). However, GS has its own limitations, including computational burden due to the amount of data generated and difficulty in interpreting novel structural or non-coding variants (Krude et al., 2021). Despite the theoretical advantages, GS is less commonly used, and its practical utility in relation to ES remains debated (Nurchis et al., 2022; Schwarze et al., 2018; Sun et al., 2021).

Here, we present 9 cases that illustrate the diagnostic utility of GS in pediatric cases of NDD with previous non-diagnostic ES. Several technical limitations of ES were represented in these cases, including poor sensitivity for structural variants and non-coding variants, and biased coverage of the coding regions.

2 |. METHODS

The cases were collected through retrospective review of the individuals enrolled at the Children’s Hospital of Philadelphia (CHOP) in the Myelin Disorders Biorepository Project (MDBP; IRB14–011236) and Pediatric Investigation of Neurodegeneration Genetics Project (PING; IRB16–013278). Informed consent was obtained from the legal guardians of all participants. These individuals underwent GS between 2017 and 2022, following non-diagnostic ES performed between 2012 and 2020. All individuals with documented non-diagnostic ES and documented diagnostic GS were included in this study. All cases with diagnostic GS without detailed documentation of prior nondiagnostic ES were excluded from this study. GS was performed by Illumina (San Diego, California) for the MDBP cohort, and by the Center for Applied Genomics (CAG) at CHOP for the PING cohort.

3 |. RESULTS

A total of nine cases were identified meeting our criteria (Table 1). We identified six cases from the MDBP cohort with diagnostic GS following documented non-diagnostic ES, out of 94 cases who underwent GS prior to 2022. We identified additional three cases from the PING cohort, out of approximately 130 individuals who underwent GS through the CAG prior to 2022, following documented non-diagnostic ES. The precise figure of all individuals who underwent GS following non-diagnostic ES in these cohorts could not be determined, due to inconsistent availability of information on their previous genetic evaluation. All individuals presented with global developmental delay or regression. Other features present in this cohort included epilepsy, white matter abnormalities, brain malformations and dysmorphic features. Cases are further detailed in the Supplemental Material.

TABLE 1.

Summary of each case, including the clinical features, diagnostic course, diagnostic variant(s), and the reason for a nondiagnostic exome.

Case # Age at diagnosis Sex Clinical presentation Year of ES Lab performing ES Microarray performed Year of GS Lab performing GS Diagnosis Mode of inheritance Diagnostic variant 1 Diagnostic variant 2 Reason for nondiagnostic ES
1 18 yrs Female Leigh-like syndrome, mild global delays, scoliosis, short stature 2018 CHOP Yes 2021 CHOP IARS2-related Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia AR IARS2, 3.7 kb deletion, chr1 (GRCh37): g.220,280,190–220,283,922, pathogenic C.2122G > A, p. Glu708Lys, VUS Deletion not detected on ES
2 9 years Female Epilepsy, mild global delays, dysmorphic features 2017 CHOP Yes 2017 CHOP DYRK1A-related intellectual development disorder AD DYRK1A, 1-exon, 5.6 kb deletion, chr21(GRCh37): g.38,853,733–38,859,396, de novo, pathogenic N/A Deletion not detected on ES
3 12 mo Male Hypotonia, global developmental delay, progressive microcephaly, spasticity, intermittent exotropia 2019 UCSF Yes 2020 Illumina SAMHD1-related Aicardi-Goutieres syndrome AR SAMHD1 C.437A > G (p.Tyrl46Cys), NM_015474.3, maternally inherited, likely pathogenic SAMHD1, 9.0 kb deletion, chr20 (GRCh37):g.35,577,194–35,586,176, paternally inherited, pathogenic Deletion not detected on ES
4 30 mo Female White matter abnormalities, developmental regression, esotropia, hypotonia, ataxia 2019 Fulgent No 2020 Illumina MAPK8IP3-related neurodevelopmental disorder AD MAPK8IP3 c.2820–3C > G, NM_001318852.1, heterozygous, de novo; the variant was predicted in silico to significantly affect the splicing (MaxEntScan: 9.35 → −8.98 (−100%); SpliceAl: 0.70); likely pathogenic N/A Gene not known to be associated with disease at the time of ES
5 7 years Female Seizures, global developmental delay, dysmorphic features, autism, severe cognitive impairment 2014, reanalysis in 2017 GeneDx No 2021 Illumina Snijders Blok-Campeau syndrome AD CHD3 C.5812G > A, NM_001005273.3, (p.Alal938Thr), de novo, likely pathogenic N/A Variant not known to be associated with disease at the time of ES
6 11 years Male Global developmental delay, abnormal tone, spasticity, dystonia, choreathetosis, nystagmus, hypothyroidism, liver involvement, calcifications in the basal ganglia 2018, reanalysis in 2020 GeneDx Yes 2022 Illumina RNU7–1-related Aicardi Goutieres syndrome AR RNU7–1 chr12 (GRCh37): g.7053018del n.40delC, NR_023317.1, homozygous, biparentally inherited, VUS N/A Insufficient coverage of non-coding RNA on ES
7 8 years Male White matter abnormalities with progressive cerebral calcifications, global developmental delay, growth delay, dystonia, dysarthria, seizuresm, strokes, hydronephrosis, and mild dysmorphic features. 2020 GeneDx No 2021 Illumina SNORD118-related leukoencephalopathy with brain calcifications and cysts AR SNORD118 chr17 (GRCh37): g.8076762G > A (n. *9C > T), NR_033294.1, paternally inherited, likely pathogenic SNORD118 chr17 (GRCh37): g.8076761_8076771del (n.136_n.*10del), NR_033294.1, maternally inherited, likely pathogenic Insufficient coverage of non-coding RNA on ES
8 7 years Male Normal development until age 7, then sudden onset and progressive neurologic symptoms including altered mental status, loss of speech, and abnormal muscle tone, with extensive white matter abnormalities. Followed by spontaneous improvement of both neurological and imaging findings. 2020 GeneDx No 2020 Illumina GJB1-related Charcot-Marie- Tooth neuropathy XLD GJB1 C.-17G > A, NM_000166.5, maternally inherited, pathogenic N/A Insufficient coverage of the promoter region on ES
9 3 years Male Global developmental delay, hypotonia, and chronic transaminitis 2016, reanalysis in 2018 CHOP Yes 2021 CHOP BCAP31-related deafness, dystonia, and cerebral hypomyelination XLR BCAP31 C.493G >T (p.Gly165Ter), NM_001139441.1, hemizygous, maternally inherited, likely pathogenic N/A Insufficient coverage of the coding exon on ES
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4 |. SINGLE-EXON DELETIONS WERE MISSED ON ES

Three cases were diagnosed on GS due to identification of relatively small pathogenic deletions missed on ES as well as chromosomal microarray (CMA; Cases 1–3). The sizes of deletions ranged from 3.0 to 9.0 kb, and all contained a single exon. Each of these cases underwent ES between 2017 and 2019, at clinical laboratories that were not validated to report copy number variants (CNVs) at the time. Each case additionally had previously undergone chromosomal microarray that did not identify the pathogenic deletions.

5 |. RECLASSIFICATION OF CODING VARIANTS BASED ON NOVEL DISEASE-GENE ASSOCIATION AND VARIANT RECLASSIFICATION

Two cases were diagnosed on GS due to identification of pathogenic or likely pathogenic coding variants within genes that were not associated with diseases at the time of initial ES (MAPK8IP3 and CHD3, Cases 4 and 5 respectively). These cases therefore would likely have been diagnosed on ES reanalysis.

6 |. NON-CODING VARIANTS MISSED ON ES

Three cases were diagnosed on GS due to identification of diagnostic variants within non-coding regions (Cases 6–8). Case 6 was found to have biparentally inherited, homozygous single nucleotide deletion (n.40delC) within RNU7–1, which encodes the U7 small nuclear RNA. This gene is not captured on typical exome platforms according to The Genome Aggregation Database (gnomAD). Although this novel variant was classified as a variant of unknown significance, it was considered diagnostic due to strong phenotypic overlap with RNU7–1 associated Aicardi-Goutières syndrome, and the proximity of the deleted nucleotide to previously reported pathogenic variants (see Supplemental Material). Case 7 was found to have compound heterozygous likely pathogenic variants within the SNORD118 gene, which encodes a small nucleolar RNA. The evidence for clinical relevance for SNORD118 predates the ES performed for this patient in 2020 (Jenkinson et al., 2016). Although this gene is captured on at least some ES platforms according to gnomAD, it was not covered sufficiently in the originally performed ES.

Case 8 was found to have a maternally inherited pathogenic variant within the promoter region (c.-17G > A) of GJB1. Pathogenic variants that disrupt the promoter region of this gene have been reported in cases of X-linked Charcot–Marie–Tooth disease (Tomaselli et al., 2017). This specific position, although closely upstream to a coding exon, fell outside of the captured region on ES. This diagnosis also led to the evaluation and identification of subtle neurological findings in the mother.

7 |. PATHOGENIC CODING NONSENSE VARIANT WAS MISSED ON ES DUE TO INSUFFICIENT COVERAGE

On GS, Case 9 was found to have a hemizygous, maternally inherited pathogenic nonsense variant c.493G > T (p.Gly165Ter) within BCAP31. This variant was not reported on ES and reanalysis, despite known disease association. Hemizygous pathogenic variants in BCAP31 results in X-linked recessive deafness, dystonia, and cerebral hypomyelination syndrome (Vittal et al., 2015). Review of the data from clinical trio ES found that the exome probe-set utilized did not sufficiently capture the relevant exon. Specifically, only 2 to 7 reads covered this nucleotide among the trio sequenced (Figure S1).

Although this diagnosis was made post-mortem (see Supplemental Material), it had immediate clinical implication as it prompted evaluation of a male fetus in the mother’s uterus at time of diagnosis. Targeted variant testing of the fetus via amniocentesis revealed that he was not affected.

8 |. DISCUSSION

Here, we report nine individuals who initially presented for evaluation of pediatric-onset NDD and were diagnosed via GS following nondiagnostic ES. Detailed review of the cases revealed varying reasons for non-diagnostic ES, with common reasons being CNVs or noncoding variants not detected on ES. For some cases, novel evidence regarding gene-disease association became available to aid interpretation in the interim between the initial ES and the GS. Notably, the ES platforms that did not detect the pathogenic CNVs were not clinically validated for CNV detection.

ES was historically used primarily for detection of single-nucleotide variants or small insertion and deletions, and additional modalities such as CMA or dedicated copy number analysis were necessary for evaluation of deletions and duplications. Modern ES and analysis, however, offers CNV detection at analytical validity comparable to CMA, and ES could detect CNVs smaller than the theoretical detection limit of CMA (Testard et al., 2022). Within our cohort, the CNVs were missed on ES performed between 2017 and 2019; these laboratories (CHOP and UCSF) have since updated the platform to include CNV analysis. Of note, the CNV sensitivity is dependent on the coverage depth of the region of interest, which in turn depends on the size and number of exons involved, if using ES platforms (Fowler et al., 2016). Single-exon CNVs therefore are theoretically more difficult to detect on ES. It is therefore possible that the single-exon CNVs seen in Cases 1–3 could have been missed on ES with CNV detection, depending on the coverage depth and the specific CNV detection algorithms used.

Periodic reanalysis between 1 and 3 years following non-diagnostic ES or GS was previously shown to improve diagnostic yield (Costain et al., 2018; Wenger et al., 2017). In our cohort, we determined that 2 of 9 cases would have been diagnosed on reanalysis alone, based on detailed literature review of evidence associated with each variant, and their publication dates (Supplemental Material). However, this assumption presumes that the initial ES platform provided sufficient coverage of the relevant regions in each case.

We detected diagnostic variants within two non-coding genes, RNU7–1 and SNORD118 on GS that were not reported following ES performed in 2020 for both patients (Cases 6 and 7). Review of typical exome coverage depth on gnomAD indicated that SNORD118 was covered on at least some exome platforms, whereas RNU7–1 was not. Exome capture technologies have historically prioritized the protein-coding genes, with suboptimal coverage of non-coding genes. This is likely not a fundamental technical limitation of ES, as exome probe sets are frequently updated to include clinically relevant non-protein-coding regions.

Case 8 was diagnosed through the identification of a pathogenic variant within the promoter region of GJB1. The pathogenicity of this variant had been established prior to the exome performed in 2020 (Tomaselli et al., 2017), indicating this variant was not reported on ES due to insufficient coverage of this position. It is unclear whether modern ES platforms would routinely cover the upstream noncoding region of GJB1.

Lastly, Case 9 was diagnosed on GS by identification of a pathogenic truncating variant within BCAP31, a protein-coding gene with established disease association (Vittal et al., 2015). We found that the relevant exon was not covered sufficiently on exome capture kit used in this case. Thus, additional reanalysis would not have detected this variant, but using a different exome platform would likely have led to diagnosis. This case illustrates the subtle differences between exome platforms that occasionally result in significant test performance discrepancies due to biased coverage (Shigemizu et al., 2015). Although alternating the ES platform in lieu of reanalyzing the coding regions is not a standard practice, GS could potentially add to the diagnostic yield in ES-non-diagnostic cases by detecting missed coding variants.

Overall, our cohort demonstrated that GS following non-diagnostic ES can lead to additional diagnoses, although majority (5 of 9) of the additional diagnoses would likely have been achieved on modern ES platforms, and two of these cases would most likely have been diagnosed on routine reanalysis. The remaining four cases were diagnosed owing to the more uniform coverage offered by GS, which has consistently shown superior sensitivity to both coding and noncoding variants compared to ES (Belkadi et al., 2015; Kingsmore et al., 2019). The precise additional diagnostic yield of GS following ES could not be calculated due to pooling from different cohorts with limited documentation of prior testing (including ES) on some individuals who underwent GS.

Grether et al. recently reported a cohort of 20 individuals with developmental or epileptic encephalopathies who underwent GS following non-diagnostic ES and CMA (Grether et al., 2023). GS in this cohort yielded 4 additional diagnoses, and all the pathogenic variants could have been detected on reanalysis alone. Despite similar clinical presentation, our cohort, in contrast, is represented by higher proportion of cases that would likely not have been diagnosed on routine reanalysis.

It is unclear whether systematic use of GS for individuals with non-diagnostic ES is practical or cost-effective, although the added diagnostic power should improve with better understanding of the clinical significance of non-protein coding and intergenic variants. Further, direct comparison of ES and GS is hindered by the differences between the various ES platforms, and frequent updates to the capture technology and analytical methods. Our experience with undiagnosed NDD cohort suggests that individuals with similar presentation could benefit from GS, either as a follow-up to non-diagnostic ES or in lieu of ES.

Supplementary Material

figure
supplemental

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health NIH T32GM008638 (TTN), NIH U54NS115052 (ALV), NIH HG013031 (KW, EJB and RAN) and a grant from the Chan Zuckerberg Initiative (EJB and RAN).

Footnotes

SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are presented within the manuscript and the supplementary materials. Additional data related to this study, within limits of study participant privacy and ethical restrictions, are available on request from the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

figure
NIHMS2015003-supplement-figure.pptx (508.4KB, pptx)
supplemental
NIHMS2015003-supplement-supplemental.docx (50.2KB, docx)

Data Availability Statement

The data that support the findings of this study are presented within the manuscript and the supplementary materials. Additional data related to this study, within limits of study participant privacy and ethical restrictions, are available on request from the corresponding author.

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