Table 1.
Bi-allelic variants in SPATA5L1 cause a neurodevelopmental disorder featuring intellectual disability, cerebral palsy, epilepsy, and hearing loss
| Family | Family 1 | Family 2 | Family 3 | Family 4 | Family 5 | Family 6 | Family 7 | Family 8 | Family 9 |
|---|---|---|---|---|---|---|---|---|---|
| Patient | 1 (proband) | 3 (proband) | 5 | 6 | 7 | 8 | 9 | 10 (proband) | 13 |
| cDNA (GenBank: NM_024063.3) | c.1304_1305del (pat.); c.121G>C (mat.) | c.734T > A (pat.); c.1398T>G (mat.) | c.1A>T (pat.); c.2066G>T (mat.) | c.515C>A (pat.); c.196G>T (mat.) | c.1973G>A (pat.); c.2176_2177del (mat.) | c.76A>G (pat.); c.1079T>C (mat.) | c.1556C>A (hom.) | c.1199C>T (hom.) | c.1676delC (pat.); c.1682T>C (mat.) |
| Protein (GenBank: NP_076968.2) | p.Ile435Argfs∗4 (pat.); p.Ala41Pro (mat.) | p.Val245Glu (pat.); p.Ile466Met (mat.) | p.Met1? (pat.); p.Gly689Val (mat.) | p.Pro172His (pat.); p.Asp66Tyr (mat.) | p.Arg658Lys (pat.); p.Val726Lysfs∗13 (mat.) | p.Thr26Ala (pat.); p.Phe360Ser (mat.) | p.Ala519Asp (hom.) | p.Thr400Ile (hom.) | p.Ala559Glufs∗33 (pat.); p.Leu561Ser (mat.) |
| Ancestry | Iraqi | European, with Ashkenazi Jewish ancestry | American; mat. ethnicity, Italian; pat. ethnicity, Italian and Afro-American | mixed European | Spanish | African American | Turkish | Kazakh | mixed, Eastern European, and Scandinavian |
| Sex | male | male | female | male | male | female | female | female | male |
| Age at diagnosis | first year of life | 32 months | 27 months | 23 years | 4 months | 9–12 months | 5 years | 7 months | 1 month |
| Hearing impairment | + | + | + | + | + | + | + | + | + |
| Spasticity | + | − | + | − | − | − | + | + | + |
| Dystonia / hypotonia | + / − | + / + | − / + | − / N/A | − / + | N/A / − | + / − | + / + | − / + |
| Pattern | spastic quadriplegia | N/A | spastic quadriplegia | N/A | N/A | N/A | spastic-dystonic tetraparesis | spastic quadriplegia | spastic quadriplegia |
| Microcephaly (HC) | + (acq., 47 cm at 6 years) | − | + (acq., 46 cm at 3 years) | − | + (acq., 45 cm at 1 year) | − | + (27 cm at birth) | + (45 cm at 6 years) | − |
| DD / ID | + profound DD | + global DD | + global DD | + severe DD | + profound DD | + | + severe DD | + profound DD / ID | + profound DD |
| Epilepsy | + | − | − | + | − | + | + | + | + |
| Dysmorphic features | − | + | − | − | − | − | − | + | + |
| Visual impairment | cortical visual blindness | − | cortical visual impairment | − | − | N/A | severe cortical visual impairment | probable cortical blindness | severe impairment |
| MRI findings | progressive CO and CB volume loss; thin CC; periventricular T2 hyperintensities; subtle GP hyperintensity bilaterally | concern for delayed myelination | delayed myelination; thin CC | CC lipoma, otherwise normal | normal | thin CC; enlarged 4th ventricle; mega cisterna magna; possible brainstem hypoplasia; possible delayed myelination | profound cortical atrophy with predominant reduction of the white matter; cerebellum and brainstem normal | paucity of periventricular WM bilaterally with patchy confluent T2 hyperintensity; thin CC; generalized CO atrophy | normal (age 14 months); repeat MRI showed diminished cortical volume |
| Family | Family 10 | Family 11 | Family 12 | Family 13 | Family 14 | Family 15 | Family 16 | Family 17 | Family 18 |
|---|---|---|---|---|---|---|---|---|---|
| Patient | 14 | 15 | 16 (proband) | 18 | 19 | 20 | 21 | 22 (proband) | 25 |
| cDNA (GenBank: NM_024063.3) | c.190C>T; c.1826C>G | c.85T>G (hom.) | c.1199C>T (pat.); c.1090−2A>G (mat.) | c.2066G>T (pat.); c.527G>T (mat.) | c.527G>T (pat.); c.2006T>G (mat.) | c.527G>T; c.1199C>T | c.213T>G; c.1313T>C (hom.) | c.1091T>A (pat.); c.1918C>T (mat.) | c.1648_1649insC; c.2066G>T |
| Protein (GenBank: NP_076968.2) | p.Arg64Trp; p.Ser609∗ | p.Cys29Gly (hom.) | p.Thr400Ile (pat.); p.? (mat.) | p.Gly689Val (pat.); p.Gly176Val (mat.) | p.Gly176Val (pat.); p.Met669Arg (mat.) | p.Gly176Val; p.Thr400Ile | p.Phe71Leu (hom.); p.Leu438Pro (hom.) | p.Val364Glu (pat.); p.Arg640∗ (mat.) | p.Phe550Serfs∗16; p.Gly689Val |
| Ancestry | African American | Turkish | European (German) | Italian | European (German) | German | Arabian | German | Italian |
| Sex | male | male | male | male | female | male | male | male | male |
| Age at diagnosis | 3 months | 14 months | 5 years | 5 years, 6 months | 2–3 months | 15 years, 6 months | 8 weeks | 14 years, 9 months | 5 months |
| Hearing impairment | + | + | + | + | + | + | + | + | + |
| Spasticity | + | − | + | + | + | + | + | + | + |
| Dystonia / hypotonia | + / + | + / − | + / + | + / + | + / + | + / + | + / + | + / + | + / + |
| Pattern | spastic quadriplegia | quadriparesis | spastic quadriplegia | spastic quadriplegia | spastic quadriplegia | hypotonic dystonic spastic quadriplegia | hypotonic dystonic spastic quadriplegia | hypotonic dystonic spastic quadriplegia | hypotonic dystonic spastic quadriplegia |
| Microcephaly (HC) | + | + (34 cm at birth) | − | + (acq.) | + (cong.) | + (−2 SD at 1 year) | + (32 cm at birth) | − | + (48 cm at 6 years) |
| DD / ID | + profound global DD | + | + profound global DD | + severe ID | + severe ID | + profound global DD | + profound global DD | + profound global DD | + profound global DD |
| Epilepsy | + | + | − | + | − | + | + | + | + |
| Dysmorphic features | − | − | − | + | − | N/A | + | − | + |
| Visual impairment | − | − | mild myopia | N/A | severe impairment | − | severe impairment | severe impairment | central visual impairment |
| MRI findings | diffusely diminished CO volumes; ex vacuo dilatation LV; delayed myelination; thin CC | bilateral peritrigonal hyperintensity | diminished CO volume; periventricular WM hyperintensity | ventricle enlargement (slight); WM hyperintensity | diffuse slightly diminished CO volume; thin CC; lactate peak visualized on MRS (2 years) | mildly diminished CO volume; mildly atrophic BG; delayed myelination of the CC | mega cisterna magna; embryonic variant posterior cerebral artery | normal (11 months); slightly enlarged ventricles (19 months); no progression of ventricular enlargement (25 months); delayed myelination, thin CC (4.5 years) | brain hypomyelination; diffuse slight brain atrophy |
Abbreviations: CO, cortical; CB, cerebellar; CC, corpus callosum; DD, developmental delay; ID, intellectual disability; GP, globus pallidus; WM, white matter; BG, basal ganglia; MRS, magnetic resonance spectroscopy; mat., maternal; pat., paternal; hom., homozygous; +, clinical feature detected; −, clinical feature not observed; N/A, no information provided for clinical feature; SD, standard deviation; p, percentile; acq., acquired postnatally; cong., congenital; HC, head circumference. T2 is an MRI signal acquisition parameter.