Table 1.
Previously undetected variants identified in re-analysis.
| Family | Affected | Gene | Variant | Inheritance mode | Gene classification | Variant classification | Explains phenotype | Phenotype |
|---|---|---|---|---|---|---|---|---|
| MR152 | 2, m | ADD3 | c.1100 G > A, p.(Gly367Asp) | AR | established | P (PS3,PM2,PM3,PP1_Moderate) | yes | ID |
| MR333 | 1, m | ADNP | c.2496_2499del, p.(Asn832Lysfs*81) | AD | established | P (PVS1,PS2_Strong,PM2) | yes | moderate ID, muscular hypotonia, gait disturbance, EEG abnormalities, cerebral atrophy |
| MR-SYR-14 | 2, fm | ASXL3 | c.4462_4465del, p.(Thr1488Serfs*17) | AD | established | VUS (PVS1_Strong,PM2,BS3) | no | mild ID, microcephaly, aggressive behavior, self-mutilation |
| MR-DIV-01 | 2, m | C12orf57 | c.1 A > G, p.0? | AR | established | P (PVS1_Moderate,PS4_Supporting,PM2,PM3,PP1_Strong) | yes | severe ID, seizures, muscular hypotonia, short stature |
| MR-SYR-49b | 1, f | DEGS1 | c.764 A > G, p.(Asn255Ser) | AR | established | P (PS3,PM2,PM3,PP1_Moderate) | yes | severe ID, cerebral atrophy |
| MR128# | 1, m | ESPN | c.1916-1 G > C, p.0? | AR | established | P (PVS1,PM2,PM3_Supporting) | partially | severe ID, muscular hypotonia, deafness, strabismus, aplasia cutis congenita of scalp |
| MR-SYR-28 | 2, fm | GCDH | c.1204 C > T, p.(Arg402Trp) | AR | established | P (PS3,PS4_Supporting,PM2,PM3_Strong,PP4) | yes | very severe ID, seizures, muscular hypotonia, limb hypertonia, spasticity, short stature, microcephaly, leukodystrophy |
| MR136 | 1, f | GRIN2A | c.2077 A > G, p.(Asn693Asp) | AD | established | LP (PS2_Moderate,PM1,PM2,PP3) | yes | very severe, EEG abnormalities, muscular hypotonia |
| MR-TUR-05 | 1, f | HNRNPH2 | c.616 C > T, p.(Arg206Trp) | AD | established | P (PS2_VeryStrong,PS4_Moderate,PM2) | yes | severe ID, myoclonus, microcephaly, muscular hypotonia, ataxia, EEG abnormalities |
| MR124 | 2, m | SCN2A | c.4606 A > G, p.(Ser1536Gly) | AD | established | VUS (PM2,PP3) | no | very severe ID, seizures, microcephaly, short stature, cataract, cryptorchidism, pyloric stenosis, cerebral atrophy, hypoplystic corpus callosum |
| MR-SYR-06 | 5, f | SLC35A1 | c.508-6 T > C, p.? | AR | established | VUS (PM2) | no | profound ID, muscular hypotonia, cerebral atrophy, seizures, short stature |
| MR073 | 3, m | TAF1 | c.2590 C > T, p.(Arg864Trp) | XL | established | LP (PM2,PP1_Moderate,PP2,PP3) | yes | moderate ID, mental deterioration, microcephaly, nystagmus |
| MR125 | 2, m | YARS1 | c.1099 C > T, p.(Arg367Trp) | AR | established | P (PS4_supporting,PM2,PM3,PP1_Strong,PP3(accordingtounpublisheddata)) | yes | ID |
| MR-SYR-49c | 1, m | ZEB2 | c.2177_2178del, p.(Ser726Phefs*29) | AD | established | P (PVS1,PM2,PP4_Moderate) | yes | severe ID, seizures, microcephaly, cerebral atrophy, hypoplastic corpus callosum, atrial septal defect, pulmonic stenosis |
| MR145 | 2, m | ZMIZ1 | c.418 T > C, p.(Ser140Pro) | AD | established | VUS (PM2,PP3) | no | moderate ID, microcephaly, short stature |
| MR-DIV-02§ | 2, fm | ZNF292 | c.3460_3463del, p.(Val1154Ilefs*7) | AD | established | LP (PVS1_Strong,PM2) | partially | mild ID, small for gestational age, short stature, microcephaly |
| MR-SYR-21 | 2, m | ARHGEF6 | c.257 A > C, p.(Asp86Ala) | XL | weak candidate | not applicable | not applicable | severe ID, limb hypertonia, microcephaly, short stature |
| MR071a | 1, f | ZNF143 | c.44_45del, p.(Glu15Valfs*25) | AR | weak candidate | not applicable | not applicable | severe ID, muscular hypotonia, recurrent infections, microcephaly |
AD autosomal dominant, AR autosomal recessive, dn de novo, EEG electroencephalogram, f female, hemi hemizygous, het heterozygous, hom homozygous, ID intellectual disability, LP likely pathogenic, m male, mat maternal, n.a. not available, P pathogenic, pat paternal, VUS variant of uncertain significance, XL X-linked; compare File S3 [12].
#: the pathogenic ESPN variant only explains part of the phenotype (deafness); §: the ZNF292 variant does not explain the microcephaly and short stature or the NDD phenotype in the other affected individuals from this family (see dual diagnosis results in Supplementary notes); *: both affected siblings inherited the ASXL3 variant from the unaffected father.