Table 1. Detailed clinical features of the individuals with nucleotide and copy number variants involving MED12L.
NA: not available, SD: standard deviation, OFC: occipital frontal circumference.
| Individual | Individual 1 (Decipher 284908) | Individual 2 (Decipher 280845) | Individual 3 (Decipher 277489) | Individual 4 SCV000611598 | Individual 5 SCV000853261 | Individual 6 SCV000853262 | Individual 7 SCV000853263 |
|---|---|---|---|---|---|---|---|
| Mutation in MED12L (according to NCBI reference sequence NM_053002.5, NC_000003.11) | g.151129252C>T, c.5992C>T, p.(Gln1998Ter) | g.150906260dup, c.1747dup, p.(Ser583PhefsTer8) | g.151097900G>A, c.4374–1G>A | g.151101870G>A, c.4686–1G>A | |||
| Size of CNV (Mb) | 460 Kb duplication | 291 Kb deletion | 147 Kb duplication | ||||
| Proximal breakpoint (Hg19) | 150,983,389 | 150,876,508 | 150,966,686 | ||||
| Distal breakpoint (Hg19) | 151,441,372 | 151,167,962 | 151,114,133 | ||||
| Inheritance | de novo | de novo | NA | NA | de novo | NA | de novo |
| Origin | France | France | France | Ukraine | USA | USA | Caucasian |
| Gender | Male | Male | Male | Female | Male | Female | Female |
| Birth term (WG) | At term | At term | 39 | NA | 37 | 32 | 39 |
| Pregnancy complications | − | Acute foetal distress at birth | − | NA | Suspected cardiac anomaly, maternal pre-eclampsia | prenatal drug exposures (cocaine, tobacco) | − |
| Birth weight (grams/SD) | 3160 (−1 SD) | 4000 (+1,5 SD) | 3630 (+1 SD) | NA | 3000 (0 SD) | 1729 (0 SD) | 2404 (−2 SD) |
| Birth length (cm/SD) | 47.5 (−2 SD) | 53 (+1.5 SD) | 50 (0 SD) | NA | 48.5 (0 SD) | 38.1 (−1.5 SD) | NA |
| OFC at birth (cm/SD) | 37 (+1.5 SD) | 35 (+1 SD) | 34 (−0.5 SD) | NA | 34 (+0.5 SD) | NA | NA |
| Age at assessment | 12 years | 22 years | 13 years 8 months | 11 years | 5 years | 8 years | 3 years 10 months |
| Weight (kg/SD) | 27 (−2 SD) | 98 (+6 SD) under neuroleptic | 47 (0 DS) | 34 (−1 SD) | 21.1 (+0.5 SD) | 22.6 (0 SD) | 13.3 (−1 SD) |
| Height (cm/SD) | 131.5 (−2.5 SD) | 185 (+2 SD) | 156 (0 DS) | 142 (−0.5 SD) | 109 (−0.5 SD) | 122.5 (0 SD) | 91.5 (−2 SD) |
| OFC (cm/SD) | 53 (−1 SD) | 57 (+1 SD) | 56 (+1.5 SD) | NA | 50.1 (−0.5 SD) | 49.5 (−1.5 SD) | NA |
| Neurological abnormalities | |||||||
| Intellectual disability | moderate | moderate | mild (IQ 74) | moderate | mild | mild | severe |
| Hypotonia | − | − | − | NA | + | − | + |
| Motor delay | + (walking at 19 months) | − (walking at 16 months) | − | NA | + (walking at 18 months) | + (walking at 20 months) | + |
| Speech impairment | + (mild, sentences at 4 yo) | + (severe, can associate words) | + (pronounciation) can make a conversation | + (speech delay) | + (pronounciation), but good vocabulary and can make a conversation | + (speech delay) | + (no language) |
| Abnormal behavior | + | ++ | + | − | + | + | + |
| Aggressive behavior | − | + | ++ | − | + | ++ | − |
| Autistic features | + | ++ | + | − | + | − | − |
| Anxiety | ++ | + | − | − | − | − | − |
| Attention deficit | − | + | − | − | + | + | − |
| Hyperactivity | − | − | − | − | + | + | − |
| Sleeping disorder | − | + | − | − | + | − | + |
| Seizures | − | − | − | − | − | staring spells | + |
| Abnormal EEG | NA | − | NA | − | − | − | + |
| Abnormal brain magnetic resonance imaging | NA | NA | NA | Agenesis of the Corpus callosum, enlargement of the posterior aspect of the right and left lateral ventricle | Mildly hypoplastic corpus callosum | Normal | Cortical signal abnormality and volume loss of bilateral putamen and globus pallidus at 3 years |
| Extra-neurological abnormalities | |||||||
| Gastro-intestinal anomalies | Chronic constipation, neonatal occlusive syndrome, encopresia | Gastroesophageal reflux | unilateral inguinoscrotal hernia | − | Feeding difficulties in early infancy, moderate chronic constipation | − | Feeding difficulties (G-tube dependent), gastroesophageal reflux, intermittent constipation |
| Congenital malformations | Unilateral coloboma of iris and retina | − | − | − | Suspected VSD prenatally but normal echocardiogram at birth, Hypospadias, voiding dysfunction | − | − |
| Skeletal abnormalities | Thoracolumbar kyphosis, hyperlaxity | − | − | Very large knees, appears to have bony prominence medially | − | − | − |
| Hands and feet anomalies | Long appearing fingers, unilateral single palmar transverse crease | Long appearing fingers | Bilateral 5th finger brachyphalangy P1, pes planus | Fingers-fetal padding, 5th hypoplastic nails | − | − | − |
| Sensory abnormalities | Hypermetropia | − | Myopia | − | − | − | Hypermetropia, strabismus |
| Other findings | − | Dilated cardiomyopathy (toxic origin) | − | Hypopigmented macules (oval shapped on right shoulder blade) | recurrent respiratory infections | − | − |
| Dysmorphic features | |||||||
| High forehead | − | − | − | − | + | − | − |
| Downslanted palpebral fissures | + | − | − | − | − | − | + |
| Fullness of the upper eyelids | + | + | − | − | − | − | + |
| Prominent nasal bridge | − | + | − | + | − | − | − |
| Bulbous nasal tip | + | − | − | − | + | − | − |
| Open mouth | − | − | − | − | − | − | + |
| High, narrow palate | − | − | − | + | − | − | + |
| Other | Unilateral ptosis, hypertelorism, sparse eyebrows | Short philtrum, everted lower lip, small mouth | − | medial eyebrow flare, inverted lower eyelid, pointed chin, high cheek bones, down-turned corners of mouth, prominent ear crease-left ear | Deep-set eyes, thin upper lip, triangular face | − | Flat nasal bridge, upturned nose |
| Other genetics investigations | |||||||
| Karyotype | normal | normal | normal | NA | 46,XY,t(9;18)(p13;q12.2) | NA | normal |
| Chromosomal microarray | duplication 22q11.2 inherited from the healthy mother | − | − | normal | arr[hg19]4q34.3(178,557,799–179,142,775)x3 (small gain on chromosome 4 in a non-disease associated region) | arr[hg19]2p16.3(51,080,824–51,193,164)x1 (intronic deletion of NRXN1) | arr[hg19]10q11.21(43,555,634–43,626,143)x3 (contains the entire coding region of RET) |
| Gene testing | − | FMR1 negative | FMR1 negative | WGS identified VUS in TUBB2B: c.43G>A; p.(Gln15Lys) | normal Fragile X testing, WES identified the variant c.2380 C>T; p.(His794Tyr) in LZTR1 paternally inherited | NRXN1 sequencing negative | PTPN11, SMN1 deletion, DNA methylation for Prader-Willi/Angelman syndrome, neuromuscular multi-gene panel : negative |
*
Nomenclature HGVS V2.0 according to mRNA reference sequence NM_053002.5. Nucleotide numbering uses +1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1.