Table 1.
Summary of patients with genetic mutations affecting TRAPPC9 and exhibiting NS-ARID.
| Mutation (GRCh37/hg19) | Mutation Type | Affected Families | Cases, Sex | Consanguineous | Major symptoms |
|---|---|---|---|---|---|
| p.Leu178Pro (c.533T>C) | Nonsense homozygous mutation in exon 2 | -Moroccan | 1 M, 1 F 82 | Likely | Severe ID, congenital microcephaly, severe language and motor delays, MRI findings (white matter abnormalities), hyperkinesia |
| p.Trp190Argfs*95 (c.568_574delTGGCCAC) | Homozygous 7 nucleotide deletion in exon 2 | -Maltese | 1 M 75 | No | ID, microcephaly, absence of speech, facial dysmorphia, MRI findings, ASD, stereotypical movements |
| Splice site defect (c.1024+1G>T) | Homozygous skip of exon 3 or exons 3 and 4 | -Pakistani | 3 F 129 | Yes | Moderate ID, microcephaly, speech and motor delay |
| p.Arg475* (c.1423C>T) | Nonsense homozygous mutation in exon 7 | -Pakistani -Pakistani -Syrian -Israeli Arab -Egyptian |
3 M 12 1 M, 6 F 7 3 M, 3 F 130 3 F 6 1 F 131 (Decipher ID 296553) |
Yes Yes Yes Yes Yes |
ID, microcephaly, speech delay Microcephaly, speech and motor delays, mild obesity, MRI findings Severe ID, moderate-severe microcephaly, severe motor and speech delay, hypotonia, severe growth retardation, stereotypic movements Severe ID, microcephaly, speech delay, MRI findings Moderate ID, microcephaly, speech and motor delay, MRI findings, facial dysmorphia, stereotypical movements |
| p.Arg500Cys (c.1498C>T) | Missense homozygous mutation in exon 8 | n/a | 1 M (unpublished; Decipher ID 262147) | n/a | Global developmental delay, brachycephaly, delayed speech developmental, mild facial dysmorphia |
| p.Arg570* (c.1708C>T) | Nonsense homozygous mutation in exon 9 | -Tunisian -Tunisian |
3 M 8 1 M, 2 F 67 |
Yes Yes |
Moderate-Severe ID, speech delay, mild microcephaly, truncal obesity, mild facial dysmorphia, MRI findings Severe ID, microcephaly, obesity, facial dysmorphia |
| p.Glu689* (c.2065G>T) | Nonsense homozygous mutation in exon 11 | -Pakistani | 2 M, 1 F 12 | Yes | Severe ID, microcephaly, speech and motor delay |
| p.Gly753Glufs*5 (c.2258del) | Nonsense homozygous mutation in exon 13 | n/a | 2 F (unpublished; Decipher ID 284294 and 284295) | n/a | Severe ID, congenital microcephaly, absence of speech, mild facial dysmorphia, stereotypic movements |
| p.Leu772Trpfs*7 (c.2311-2314delTGTT) | Homozygous out of frame 4 nucleotide deletion in exon 14 | -Iranian | 3 M 7 | Yes | ID, microcephaly, absence of speech, obesity |
| p.Arg929* (c.2785C>T) | Nonsense homozygous mutation in exon 19 | n/a | 1 M 132 | Yes | ID, microcephaly, global developmental delay, abnormal gait, facial dysmorphia, MRI findings (including reduced myelination) |
| p.Thr951Tyrfs*17 (c.2851-2A>C) | Homozygous splice variant causing skip of exon 18 leading to frameshift | -Italian | 2 F 62 | No | Severe ID, hypotonia, seizures, microcephaly, facial dysmorphia, speech and motor delay, MRI findings (white matter abnormalities), obesity |
| p.Arg1072* (c.3214C>T) | Nonsense homozygous mutation in exon 20 | -Indian | 1 F 133 | Yes | ID, primary microcephaly, Moderate-Severe global developmental delay, truncal obesity, MRI findings, stereotypic movements |
| 8q24.3 microdeletion | Homozygous 141 kb deletion in subtelomeric region of 8q24.3 deleting only TRAPPC9 | -Filipino | 1 F 11 | Yes | Severe ID, microcephaly, MRI findings, facial dysmorphia, severe motor and speech delay, hypotonia, obesity |
| Intragenic tandem duplication | Homozygous 115 kb intragenic tandem duplication | -Algerian | 1 F 67 (Decipher ID 349431) | Yes | Moderate-Severe ID, microcephaly, MRI findings, facial dysmorphia, obesity, stereotypic movements |
| p.Trp190Argfs*95 (c.568_574delTGGCCAC) and duplication | Maternally inherited 7 nucleotide deletion in exon 2 and paternally inherited 119 kb in-frame intragenic duplication | -Italian | 1 F 67 (Decipher ID 314942) | No | Moderate-Severe ID, microcephaly, MRI findings, facial dysmorphia, obesity, stereotypic movements |
| p.Arg712* (c.2134C>T) and deletion | Paternally inherited heterozygous nonsense variant in exon 12 and maternally inherited 189 kb intragenic deletion | -French | 1 F 67 | No | Moderate-Severe ID, microcephaly, MRI findings, facial dysmorphia, obesity, stereotypic movements |
| p.His806Profs*9 and splice site defect (c.2415_2416insC, c.3349+1G>A) | Compound heterozygous mutations in exon 15 (nonsense) and intron 21 (splice variant) | -Thai | 1 M 74 1 F 74 |
No No |
ID, developmental delay, microcephaly autism spectrum disorder (ASD), cleft lip |
| p.Arg475* and splice site defect (c.1423C>T, c.3350-2A>G) | Compound heterozygous mutations in exon 7 (nonsense, maternal) and intron 21 (splice variant, paternal) | -European | 1 M 134 | Yes | ID, global developmental delay, speech and motor delays, microcephaly, MRI findings including myelination defects, facial dysmorphia |
| Compound splice site defects (c.2148+1G>A, c.2851-1G>C) | Compound heterozygous mutations in intron 12 (maternal) and intron 17 (paternal) | n/a | 1 F (unpublished; Decipher ID 271665) | n/a | Severe global developmental delay, microcephaly childhood-onset truncal obesity, facial dysmorphia, stereotypic movements |
| p.Arg570* and p.Arg500Cys (c.1708C>T, c.1498C>T) | Compound heterozygous mutations in exon 9 (nonsense, maternal) and exon 8 (missense, paternal) | n/a | 1 M (unpublished; Decipher ID 277516) | n/a | Global developmental delay, absence of speech, facial dysmorphia |
| p.Ser569Pro, p.Arg570Profs*80; p.Asn758Thrfs*22 (c.1705C>T, c.1708dupC, c.2273delA) | Compound heterozygous nonsense mutations in exon 9 (maternal) and exon 13 (paternal) | -Chinese | 1 M 135 | n/a | ID, language delay, abnormal MRI findings including dysplasia of corpus callosum |
Note: To date, 26 families with a total of 55 patients have been identified, with most being from consanguineous families. Clinical symptoms seen in all patients include moderate to severe intellectual disability, speech disorder, postnatal microcephaly, dysmorphic facial features, obesity, hypotonia, and brain white matter abnormalities.