Table 2 Details of the 9/36 Individuals that were resolved by bioinformatics reanalyses of pre-UDN ES data and phenotyping
Individual number and phenotype | Pre-UDN ES | Reason for pre-UDN negative ES a | Duke/Columbia bioinformatics reanalyses and annotation of gene/variants | Certainty of diagnosis and details | ||
|---|---|---|---|---|---|---|
1 | 14-year-old Caucasian female with growth failure, metaphyseal dysplasia, and thrombocytopenia | Research | Variability in laboratory reporting (prioritization) | Research lab identified variant, did not prioritize due to focus on de novos | EFL1 c.379A>G p.T127A Tier 1 newly homozygous | Certain Shwachman–Diamond-like syndrome |
2 | 18-year-old Caucasian female with hemiplegic migraine, hypotonia, ataxia, cerebellar atrophy, and severe intellectual disability | Research | Analytical approach (technical limitation) | Not detected by research laboratory due to unknown reasons | CACNA1A c.4055G>T p.R1352L Tier 1 de novo in HZ [E] and HZ [OMIM]. Variant previously in ClinVar | Certain Epileptic encephalopathy, early infantile, 42 (MIM 617106) |
3 | 14-year-old Caucasian male with renal failure due to nephronophthisis, retinal dystrophy, and cerebellar ataxia | Research | Analytical approach (technical limitation of ES in CNV detection) | Homozygous deletion of NPHP1 gene not easily amenable to ES | NPHP1 b Homozygous deletion CNV calling with GATK4 on exome | Certain Nephronophthisis, familial juvenile (MIM 256100) |
4 | 8-month-old Caucasian male with congenital hypotonia, muscle weakness, fine tremor, laryngomalacia and motor delay | Commercial | Variability in laboratory reporting (interpretation) | Not reported by clinical lab because phenotype not thought to be a good fit due to lack of arthrogryposis | MYBPC1b c.776T>C p.L259P Tier 1 de novo in HZ [OMIM] | Highly Likely Phenotypic expansion of distal arthrogryposis, type 1B (MIM 614335); three other similar patients identified, all with congenital hypotonia, tremors that have improved over time, with normal cognition |
5 | 20-month-old Caucasian male with infantile spasms, microcephaly, lamellar cataracts, failure to thrive, and global developmental delay | Commercial | Knowledge gap (gene–disease relationship not established) | Reported as candidate gene with VUS | NACC1 c c.892C>T p.R298W Tier 1 de novo in HZ [E] | Certain Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (MIM 617393) |
6 | 16-month-old Caucasian female with axonal motor neuron disease and cerebellar atrophy | Commercial | Knowledge gap (gene–disease relationship not established) | Reported as candidate gene with VUS | AGTPBP1 d c.2492-1G>T IVS16-1G>T c.2892delC p.Y964X LoF variants in LoF depleted gene | Certain Infantile-onset degeneration of central and peripheral nervous systems; nine other patients identified |
7 | 6-year-old Caucasian male with developmental delay, hypotonia, followed by progressive neurological regression | Research | Unknown reasons | Not reported for unknown reasons | IRF2BPL d c.514G>T p.E172X Tier 1 de novo LoF in LoF depleted gene | Highly Likely IRF2BPL associated neurodegenerative disorder; six patients identified with similar phenotypes |
8 | 7-year-old Caucasian female with epilepsy, hypotonia, profound intellectual disability, cortical visual impairment Subsequently found to have prolonged QT interval | Commercial | Variability in laboratory reporting (interpretation) | Not reported by clinical lab because phenotype not thought to be a good fit, due to lack of syndactyly and electrocardiographic abnormalities | CACNA1C b c.4087G>T p.V1363L Tier 1 de novo in HZ [E] and HZ [OMIM]. | Highly Likely Timothy syndrome (MIM 601005); diagnosis on patient supported by additional phenotyping with ECG and Holter monitoring. Three other similar patients identified who presented with epilepsy, intellectual disability, no syndactyly, and on further investigation 2/3 had long QT interval, thus representing likely phenotypic expansion of disorder (electrographic investigations pending in third patient) |
9 | 10-year-old Caucasian female with developmental delay, microcephaly, hypotonia, minor dysmorphic features, conductive hearing loss | Research | Knowledge gap (gene–disease relationship not established) | Not reported due to lack of disease association | HNRNPK b c.173T>C p.I58T Tier 1 de novo | Tentative Au-Kline syndrome (MIM 616580). Functional studies of variant pending |
