Table 1.
Clinical features of affected individuals with TIAM1 variants
| Proband 1 | MZ twin of proband 1 | Proband 2 | Proband 3 | Proband 4 | |
|---|---|---|---|---|---|
| TIAM1 variant (GenBank: NM_001353694.2) | c.67C>T (p.Arg23Cys); c.2584C>T (p.Leu862Phe) | c.67C>T (p.Arg23Cys); c.2584C>T (p.Leu862Phe) | c.983G>T (p.Gly328Val) | c.4640C>A (p.Ala1547Glu) | c.1144G>C (p.Gly382Arg); c.4016C>T (p.Ala1339Val) |
| Genomic DNA, GRCh38 | 21:31266906 G>A; 21:31187079 G>A | 21:31266906 G>A; 21:31187079 G>A | 21:31252170 C>A | 21:31120504 G>T | 21:31252009 C>G; 21:31130242 G>A |
| CADD score | 29.1; 23.7 | 29.1; 23.7 | 25.4 | 18.1 | 23.9; 26.7 |
| Allele frequency (gnomAD) | 4.04e−4; 3.98e−6 | 4.04e−4; 3.98e−6 | 8.18e−6 | 0 | 5.66e−5; 3.98e−6 |
| Zygosity | compound heterozygous | compound heterozygous | homozygous | homozygous | compound heterozygous |
| Sex | M | M | M | M | F |
| Current age | 35 years | 35 years | 3 years | 7 years | 6 years |
| Developmental delay | + | + | + | + | + |
| Intellectual disability | + | + | N/A | + (severe) | + (severe) |
| Delayed speech | + | + | + | + (non-verbal) | + (severe) |
| Autism | + | + | N/A | N/A | N/A |
| ADD/ADHD | + | + | N/A | N/A | N/A |
| Seizures | + | + | +, complex febrile seizures (abnormal EEGs) | + | + (severe) |
| Brain MRI | N/A | N/A | progressive macrocephaly (secondary to chronic subdural hematoma and extra-axial fluid) | diffuse cerebral atrophy; thin corpus callosum; hypomyelination; deep cortical sulcus | hypothalamic hamartoma |
| Other neurological symptoms | none | impulsive, obsessive behavior | axial hypotonia; appendicular hypertonia | none | N/A |
| Endocrine symptoms | hypothyroidism; Addison’s disease | hypothyroidism | subclinical hypothyroidism | hypomagnesemia | N/A |
| Other | none | none | dysmorphic features; congenital heart defect (atrial and ventricular septal defects); undescended testes | poor growth (difficulty in gaining weight); undescended testis; hirsutism | none |
| Consanguinity | none | none | + | + | none |
MZ, monozygotic; CADD, combined annotation dependent depletion; M, male; N/A, not available; ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; EEG, electroencephalography.