CaseAC007_II-1: Male, 5 yrs onset, Liberia, Black

CasePresentingHPOs: HP:0001992, HP:0002373, HP:0010864, HP:0000729, HP:0000750, HP:0002539, HP:0002282 (Organic aciduria, Febrile seizure, Severe intellectual disability, Autistic behavior, Delayed speech and language development, Cortical dysplasia, Gray matter heterotopia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are reportedly non-consanguineous, Proband is confirmed homozygous for this variant without parental confirmation via restriction fragment analysis

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed. Restriction digest analysis was performed to confirm homozygosity.

Variant: NM_000666.3(ACY1):c.1156C>T (p.Arg386Cys)

ClinVar: 712435, https://www.ncbi.nlm.nih.gov/clinvar/variation/712435/

gnomAD: 0.01775 (3 homozygotes), https://gnomad.broadinstitute.org/variant/3-52023020-C-T

CaseAC014_II-1: Female, 3 yrs report, Lebanon

CasePresentingHPOs: HP:0001992, HP:0025356 (Organic aciduria, Psychomotor retardation)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is confirmed homozygous for this variant via parental testing, Siblings are healthy

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed.

Variant: NM_000666.3(ACY1):c.1132C>T (p.Arg378Trp)

ClinVar: 493363, https://www.ncbi.nlm.nih.gov/clinvar/variation/493363/

gnomAD: 0.00001499 in ExAC, https://gnomad.broadinstitute.org/variant/3-52022996-C-T?dataset=exac

CaseAC014_II-1: Female, 3 yrs report, Lebanon

CasePresentingHPOs: HP:0001992, HP:0025356 (Organic aciduria, Psychomotor retardation)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is confirmed homozygous for this variant via parental testing, Siblings are healthy

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed.

Variant: NM_000666.3(ACY1):c.1132C>T (p.Arg378Trp)

ClinVar: 493363, https://www.ncbi.nlm.nih.gov/clinvar/variation/493363/

gnomAD: 0.00001499 in ExAC, https://gnomad.broadinstitute.org/variant/3-52022996-C-T?dataset=exac

CaseOS-124_II-1: Male, Birth onset, Turkey

CasePresentingHPOs: HP:0001992, HP:0001263, HP:0002275, HP:0001252, HP:0002079, HP:0001320, HP:0002188, HP:0003396, (Organic aciduria, Global developmental delay, Poor motor coordination, Muscular hypotonia, Hypoplasia of the corpus callosum, Cerebellar vermis hypoplasia, Delayed CNS myelination, Syringomyelia,

HPOsFreeText: Syringomyelia length of 3.5 cm

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Parents are consanguineous, Older sister are unaffected, This variant results in a splicing alteration in the acceptor site of Exon 6, skipping exon 6 (amino acid residues 121 to 146) and causing a premature stop codon; Proband is confirmed homozygous via parental testing

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Values of excreted AAs are in Table 1; MRI of the head and spine was performed at age 3 mo

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant: NM_000666.3(ACY1):c.360-1G>A

ClinVar: 18112, https://www.ncbi.nlm.nih.gov/clinvar/variation/18112/

gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/3-52020270-G-A