Table 1.
Clinical and Genetic Characteristics of Affected Individuals with Candidate Variants in Lysine Methyltransferases and Demethylases
| Gene | Sex (Age at Study) | Individual Number | Genomic Position (hg19) | cDNAa(Protein Consequence) or Deletion Size | Inheritance or Zygosity | Perinatal History | DD or ID | Neuropsychiatric Disorders and CNS Anomalies | Malformations and Anomalies | Height (SD)/ Weight (SD)/ OFC (SD) | CD | Other Medical Issues |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| KMT2B | F (11 y) | 1 | 19:36212057 | c.1808dupC p.(Leu604Profs∗72) | DN Het | IUGR and feeding difficulties | severe | abnormal gait and behavioral problems | PDA, long & narrow hands, broad halluces | SS (−2.7)/ LW (−2.9) Mi (−3.34) |
yes | nystagmus, gastrostomy, urinary incontinence, constipation and growth hormone deficiency |
| KMT2C | F (17 y) | 2 | 7:151884849 | c.4744G>T p.(Gly1582∗) | DN Het | no | severe | elective mutism | duplicated right thumb and left preauricular tag | SS (−2.1) LW (−2.74) Mi (−2.42) |
yes | hearing loss and delayed puberty |
| F (4 y) | 3 | 7:151873688-151873689 | c.8849_8850delAT p.(His2950Argfs∗17) | DN Het | hydrocephalus and Dandy-Walker anomaly | severe | hydrocephalus and hypoplasia of cerebellar vermis | no | SS (−2) LW (−2) Mi (−1.97) |
yes | no | |
| F (5 y) | 4 | 7:151836279 | c.14526dupG p.(Pro4843Alafs∗12) | DN Het | no | severe (motor delay was mild) | autistic traits, developmental regression, insensitivity to pain and abnormal gait | no | N (0.4) N (0.18) N (−1) |
yes | constipation | |
| ASH1L | F (13 y) | 5 | 1:155449628 | c.3033delA p.(Val1014Cysfs∗24) | DN Het | feeding difficulties | mild | behavioral problems | bicuspid AV, VSD and PFO | N (0.2) N (0.82) N (1.16) |
yes | hypermetropia, precocious puberty and hypermobility |
| M (9 y) | 6 | 1:155322602 | c.7276C>T p.(Arg2426∗) | DN Het | feeding difficulties and hydronephrosis | severe | seizures, autistic traits and hypotonia. | cryptorchidism and inguinal hernia | N (1.6) O (2.33) N (1.36) |
yes | hypermetropia, hyperacusis and hypermobility | |
| M (7 y) | 7 | 1:155271366-155804269 | 532.9 Kb | DN | no | severe | behavioral problems | cryptorchidism and blocked nasolacrimal duct | N (−0.59 SD) N (−0.44 SD) Mi (1.72SD) |
yes | constipation | |
| KMT5B | F (13 y) | 8 | 11:67953337 | c.219delC p.(Ala74Profs∗10) | DN Het | no | moderate | autistic traits | no | TS (2.91) N (0.9) Ma (4.43) |
yes | hypermobility |
| M (19 y) | 9 | 11:67941365 | c.559C>T p.(Arg187∗) |
DN Het | no | severe | seizures,hypotonia and autistic traits | no | N (0.74) N (0.9) N (1.93) |
yes | no | |
| M (14 y) | 10 | 11:67888021-68287033 | 399.01 Kb | DN | no | mild | seizures, enlarged right ventricle and white matter signal alterations | no | N (0.63) Ma (2) |
yes | strabismus and scoliosis | |
| M (16 y) | 11 | 11:67550395-68389391 | 839 Kb | DN | no | mild to moderate | no | cryptorchidism, pectus excavatum, and overlapping 2nd and 3rd toes | N (1.68) N (0.24) N (1.87) |
yes | strabismus, diabetes mellitus and hypermobility | |
| KDM5B | M (18 y) | 12 | 1:202700104 | c.4109T>G p.(Leu1370∗) |
Mat & Pat Hom |
feeding difficulties | severe | abnormal gait and agenesis of corpus callosum | inguinal hernia and camptodactyly of 4th and 5th fingers | N (−0.23) LW (−1.52) N (−1.66) |
yes | myopia and astigmatism |
| M (10 y) | 13 | 1:202711635 1:202731850 |
c.2475-2A>G; c.895C>T (p.Arg299Ter) | Mat & Pat CoHet |
no | moderate | no | dolichocephaly and supernumerary nipple | N (0.98) N (0.51) N (0.26) |
no | no | |
| M (11 y) | 14 | 1:202702532 1:202736143 |
c.3906delC, (p.Asn1302Lysfs∗45) c.622dupT (p.Tyr208Leufs∗5) | Mat & Pat Het |
feeding difficulties, | moderate | no | atrial septal defect, cryptorchidism, hypospadias and camptodactyly of 4th and 5th fingers | N (−0.09 SD) N (−1.05) |
yes | myopia and strabismus |
Abbreviations: AV = aortic valve; CNS = central nervous system; CD = craniofacial dysmorphisms; CoHet = compound heterozygous; DD = developmental delay; DN = de novo; F = female; Het = heterozygous; Hom = homozygous; ID = intellectual disability; IUGR = intra-uterine growth retardation; LW = low weight; M = male; Ma = macrocephaly; mat = maternal; Mi = microcephaly; N = normal/not present; O = overweight; PDA = patent ductus arteriosus; OFC = occipitofrontal circumference; PFO = patent foramen ovale; SD = standard deviation; SS = short stature; TS = tall stature; VSD = ventricular septal defect; y = years.
The transcript IDs are KMT2BNM_014727.2; KMT2CNM_170606.2; ASH1L ENST00000368346.7; KMT5BNM_017635.4; and KDM5BNM_001314042.1.