Case1: Male, 3 months onset, China, Asian

CasePresentingHPOs: HP:0011968, HP:0001290, HP:0001263, HP:0001508, HP:0000023, HP:0002793, HP:0004691, HP:0001999, HP:0000369, HP:0000218, HP:0000954, HP:0006802, HP:0100952, HP:0002079, HP:0002151, HP:0012736, HP:0002421 (Poor feeding, Generalized hypotonia, Psychomotor delay, Poor weight gain, Inguinal hernia, Abnormal pattern of respiration, 2-3 toe syndactyly, Dysmorphic facies, Low-set ears, High-arched palate, Transverse palmar crease, Abnormality of the anterior horn cells, Enlarged lateral sulcus, Thinning of the corpus callosum, Increased serum lactate, Profound global developmental delay, Poor head control)

HPOsFreeText: 3 kg birth weight, Breath-holding spells, The parameters at 5 months were as follows: weight, 4 kg (<0.4th percentile); length, 58 cm (<0.4th percentile), head circumference, 36.5 cm (<0.4th percentile), Enlarged anterior portion of bilateral ventricles and thinning surrounding whiter, Abnormal infant EEG

CaseNotHPOs: HP:0001946, HP:0003542, HP:0000364, HP:0003457 (Ketosis, Increased serum pyruvate, Hearing abnormality, EMG abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, parental heterozygosity is confirmed, Both variants are predicted to destroy normal splicing sites and cause a null protein with Variant 1 skipping exon 4 and Variant 2 skipping exon 12

CasePreviousTesting: Mild elevation of hydroxyl-C4-carnitine (0.79; reference: 0.03–0.70), Normal venous blood lactate at 3 months (1.1 mmol/L; reference 0.44–1.78 mmol/L) and elevated at 5 months (3.2 mmol/L; reference: 1.42–1.90 mmol/L), Ketone and pyruvate levels at 5 months were normal, Karyotype analysis was performed to confirm normality. Low-coverage massively parallel CNV sequencing was used to confirm any copy number variation, which showed normal results.

CaseGenotypingMethod: Genomic DNA was extracted from lymphocytes and whole exome sequencing was performed. The identified variants were filtered for pathogenicity and confirmed via Sanger sequencing. cDNA sequence analysis was also performed to determine the effect of these variants on the protein.

Variant1: NM_014362.3:c.304+3A>G (p.=)

CAID: CA913203579 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203579

gnomAD: Not in gnomAD

Variant2: NM_014362.3:c.1010_1011+3delTGGTA

CAID: CA2027408 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_014362.3%3Ac.1010_1011%2B3delTGGTA

gnomAD: Not in gnomAD