Table 2. Variants identified in novel XLID genes and candidates.
| Family ID | Gene | Variant | PS score | C score | Additional information (numbers indicate informative affected/unaffected males tested for segregation/obligate female carriers) | Summary of clinical information for families per gene |
|---|---|---|---|---|---|---|
| Likely pathogenic variants in novel and validated XLID genes | ||||||
| MRX4961/L19 | CLCN4 | p.Asp15Serfs*18 | 20 | 36 | 4/2/2, F, encodes a proton-chloride antiporter | Non-specific borderline to profound ID |
| MRX1562/T8 | CLCN4 | p.Gly731Arg | 8 | 29 | F, cytosolic cystathionine-β-synthase domain, may impair transporter opening | |
| N70 | CLCN4 | p.Gly78Ser | 14 | 25 | 1/0/1, F, transmembrane domain | |
| AU27 | CLCN4 | p.Leu221Val | 8 | 25 | 2/0/4, F, transmembrane domain | |
| AU9 | CLCN4 | p.Val536Met | 14 | 27 | 3/0/7, F, transmembrane domain | |
| P180 | CNKSR2 | p.Asp152Argfs*8 | 20 | 19 | 3/0/1, F, C, encodes connector enhancer of kinase suppressor of Ras 2, interacts with PSD95, XLID protein DLG3, ID/autism protein SHANK3 | ID, attentional problems, hyperactivity, language loss, seizures99 |
| P58 | FRMPD4 | p.Cys618Valfs*8 | 20 | 38 | 5/2/2, encodes FERM and PDZ domain containing 4, interacts with PSD95, with ARHGEF7, a guanine nucleotide exchange factor with a role in the regulation of spine morphogenesis, and with actin filaments104, 123 | Mild to severe ID with variable seizures, lack of speech or poor speech, behavioral problems |
| L87 | FRMPD4 | p.Cys553Arg | 4 | 16 | De novo | |
| D60 | KLHL15 | p.Tyr394Ilefs*61 | 20 | 33 | 8/1/4, encodes kelch-like 15, large family with 8 affected in three generations | Mild to moderate ID, mild facial features |
| MRXS666/AU10 | LAS1L | p.Ala269Gly | 10 | 18 | 5/0/19, C, encodes Las1-like, ribosome biogenesis | Wilson-Turner syndrome,66 mild to moderate ID, obesity, facial features, speech impairment, variable behavioral problems, gynecomastia, small/undescended testes/hypogonadism, tapering fingers |
| T50 | LAS1L | p.Arg415Trp | 11 | 14 | 3/2/3, C | |
| MRX61/T11 | RLIM | p.Pro587Arg | 11 | 13 | 3/1/3, encodes ring finger protein, LIM domain interacting, E3 ubiquitin-protein ligase, binds to transcription factors that play important roles for the development of neuronal structures and cell types | Non-specific mild to profound ID in two families with variable behavior problems, ID, microcephaly, micrognathia and cryptorchidism in all affected of one family |
| D72 | RLIM | p.Arg387Cys | 12 | 12 | 1/2/8 | |
| AU31 | RLIM | p.Arg599Cys | 14 | 18 | 2/3/3 | |
| D177 | USP27X | p.Ser342Argfs*14 | 20 | 10 | 3/0/2, encodes ubiquitin-specific peptidase 27, interacts with USP22 which deubiquitinates core histones H2A and H2B, USP22 interacts with ARID gene KIF7 | Borderline to moderate ID, variable absent or poor speech and behavioral problems |
| L75 | USP27X | p.Tyr381His | 12 | 11 | 1/1/2, this residue is part of a domain (IPR001394) and using HOPE web server (see URLs) the variant is predicted to cause an empty space in the core of the protein or protein complex and to cause loss of hydrophobic interactions | |
| Potentially deleterious changes in novel candidate genes | ||||||
| L56 | CDK16 | p.Trp326Valfs*5 | 20 | 37 | 4/1/3, encodes cyclin-dependent kinase 16, also known as PCTK1, PCTAIRE1, and PCT-1 | ID, spastic paraplegia |
| N67 | TAF1 | p.Asn493Asp | 13 | 19 | 2/0/2, encodes TATA box binding protein (TBP)-associated factor, 250 kDa, subunit of TAFIID which plays a key role transcription initiation. Drosophila homolog phosphorylates histone H2B, variants in TAF2 cause ARID78, 79 | Mild to severe ID, facial features |
| D185 | TAF1 | p.Arg1190Cys | 14 | 27 | 2/4/7 | |
Abbreviations: C, clinical evidence; F, functional evidence from this study; HGMD, Human Gene Mutation Database; ID, intellectual disability; PS, prioritization score, includes type of variant, evolutionary conservation and predictions from Polyphen2 and SIFT; C score obtained by using Combined Annotation-Dependent Depletion (CADD);35 XLID, X-linked intellectual disability.