Table 1
Clinical and genetic features of the patients.
| # | Sex-Age | Clinical Features | Karyotype | aCGH Results | Size (kb) |
|---|---|---|---|---|---|
| 1 | M-4 | DD, hypotonia, short stature, microcephaly, micrognathia, small mouth, proximally placed thumb, fifth finger clinodactyly, broad forehead, strabismus, uplanting palpebral fissures, scoliosis | 46,XY | 1721.32q21.33 (47,346,528–48,900,875)×3 | 1554 |
| 2 | M-6 | DD, epilepsy, uncal dysplasia | 46,XY | Xp11.23 (48,888,996–49,401,262)×2 Xq21.31q21.32 (91,579,532–92,176,985)×2 | 512 |
| 3 | M-1 | DD, IUGR, short stature failure to thrive, microcephaly, round face, low-set ears, epicanthus, hypotonia, cat-like cry | 46,XY | 5p15.33p15.2 (113,576–14,739,104)×1 | 14,625 |
| 4 | M-6 | DD, VSD, curly eyelashes, thin upper lip, prominent methopic suture, synophrys, triangular face, large ears, epilepsy | 46,XY | 8q24.21q24.3 (130,459,411–140,444,375)×1 | 9985 |
| 5 | F-5 | DD, epilepsy | 46.XX.der(8) t(8,9)(p23.1; p23) | 8p24.3p23.1 (158,048–10,161,482)×1 9p24.3p23 (203,861–13,947,653)×2 | 10,003 13,744 |
| 6 | F-3 | DD, short stature, failure to thrive, hypotonia, large ears, depressed nasal bridge, thin upper lip, epilepsy | 46,XX | 2q12.2q12.3 (106,925,594–188,257,773)×3 | 50,379 |
| 7 | F-3 | DD, bifid thumb, microcephaly, strabismus, broad nasal tip, depressed nasal bridge, telecanthus, short neck, low-set ears, epilepsy | 46,XX,dup(4) (q28.2q35.1 | 4q28.2q35.1 (137,877,879–188,257,773)×3 | 50,379 |
| 8 | F-1 | DD, microcephaly, short stature, IUGR, prominent glabella, short philtrum, strasbismus, hypertelorism, epicanthus, epilepsy | 46,XX | 4p16.3 (68,345–1,881,435)×1 | 1800 |
| 9 | F-4 | DD, short stature, micrognathia, low-set ears, hyperterlorism, short philtrum, hypocalcemia | 46,XX | 23q11.21 (18,894,820–20,311,733)×1 | 1416 |
| 10 | M-1 | DD, microcephaly, hypertonicity, epilepsy | 46,XY,der(3) (p25;q25)pat | 3p26.3p26.1 (61,891–5,528,884)×1 3q25.32q29 (156,235,115–197,851,986)×3 | 5467 41,617 |
| 11 | F-1 | DD, hypotonia, iris coloboma | 46,XX | 15q13.1q13.3 (29,013,163–32,915,723)×1 | 3900 |
| 12 | F-4 | DD, epilepsy, ataxia, broad nasal tip | 46,XX | 6q21q23.31 (114,502,807–121,158,975)×1 | 6656 |
| 13 | F-1 | DD, hypotonia, brachycephaly, long eyelashes, small philtrum, telecanthus, pectus excavatum | 46,XX | Xp22.2 (11,279,310–12,016,067)×4 | 737 |
| 14 | M-10 | DD, epilepsy | 46,XY | 9q13q21.11 (68,240,211–70,984,588)×1 | 2744 |
| 15 | M-3 | DD, sensorineural hearing loss, ptosis, microcephaly | 46,XY | 9p24.3 (204,193–500,584)×3 | 296 |
| 16 | F-10 | DD, ASD, microcephaly, hypertonicity, self mutilation, optic atrophy, EEG abnormality | 46,XX | 16p12.2 (21,601,714–21,816,543)×1 | 215 |
| 17 | F-8 | DD, epilepsy, hypertonicity, hydrocephaly, obesity, short stature | 46,XX | 3p12 (44,626,845–45,983,652)×1 | 1357 |
| 18 | F-10 | DD, webbed neck, epilepsy, tall stature | 46,X,der(X) | Xp22.2p21.3 (14,036,105026,666,672)×3 | 126 |
| 19 | M-6 | DD, ADHD, VSD, epilepsy, hypotonia, microcephaly | 46,XY | Yp11.32q11.223 (118,546–25,415,912)×2 | 25,287 |
| 20 | F-7 | DD, pachygyria, lissencephaly, microcephaly, hypertonicity, epilepsy | 46,XX | 8q24.23 (137,278,410–138,539,014)×3 | 1261 |
| 21 | M-4 | DD, microcephaly, epilepsy, hypertonicity, macrodontia, optic atrophy, limb contractures | 46,XY | 16p13.11p12.3 (16,295,900–16,873,547)×1 | 578 |
| 22 | F-3 | DD, microcephaly | 46,XX | 14q32.33 (106,505,480–107,285,437)×1 | 780 |
| 23 | F-2 | DD, ASD, microcephaly, epilepsy, cone dystrophy | 46,XX | 8p1.21p11.1 (42,908,376–43,822,214)×3 | 914 |
| 24 | F-1 | DD, microcephaly, short stature, failure to thrive, prominent metopic suture, synophrys, asymetric head shape, triangular and asymetric face, telecanthus, epicanthal folds, down-slanting palpebral fissures, microphthalmia of the left eye, anteverted nares, smooth and tented philtrum, microretrognathia, low-set ears, auricular pits, high-arched palate, thin upper lip and hypotonia | 46,XX,der(16) (q24) | 16q121q23.5 (52,459,169–82,285,105)×3 | 29,800 |
| 25 | F-2 | DD, microcephaly, short stature, low-set ears, convex nasal ridge | 46,XX | 3p14.2 (60,681,991–61,207,077)×1 | 520 |
| 26 | F-14 | ID, obesity, behavioral problems | 46,XX | 8p21.3 (21,157,621–22,987,837)×3 | 1800 |
| 27 | M-12 | ID, impaired social interactions | 46,XY | 15q13.3 (31,999,631–32,914,239)×3 | 446 |
| 28 | M-3 | DD, epilepsy | 46,XY | 16p13.1 (14,866,283–16,391,910)×1 | 1500 |
| 29 | F-7 | ID, ASD, short stature, hand stereotypies | 46,XX | 14q32.2q32.33 (97,377,993–107,282,437)×3 | 9904 |
| 30 | F-4 | DD, epilepsy | 46,XX | 20p13 (2,911,855–4,931,592)×3 | 2020 |
| 31 | M-14 | ID, IUGR, hypotonia, microcephaly, short stature, low-set ears, small mouth, prominent forehead, hypertelorism | 46,XY | 19p13.3 (2,572,666–4,192,224)×3 | 1619 |
| 32 | M-25 | ID, diabetes mellitus, renal cysts, obesity, stereotyped movements | 46,XY | 15q11.2q13.1 (23,164,31–28,530,182)×3 | 5365 |
| 33 | F-4 | DD, epilepsy, microcephaly, micrognathia | 46,XX | 4q34.2q34.3 (177,322,096–180,306,130)×3 | 2984 |
| 34 | M-14 | DD, synophrys, thin upper lip, short fingernails | 46,XY,der(10) t(10;13)(p15; p11) | 10p15.3p15.1 (135,608–6,054,675)×1 | 5919 |
| 35 | M-12 | DD/ID, microcephaly, cerebral atrophy, synophrys, flat philtrum, 2-3-4-5 toe syndactyly | 46,XY | 2q31.1q31.3 (170,694,601–182,623,003)×1 | 11,900 |
| # | Sex-Age | OMIM Genes (n) | Critical Genes | Inheritance | Classification | Recurrent Microdeletion/Duplication Syndrome |
|---|---|---|---|---|---|---|
| 1 | M-4 | 25 | PPP1R9B, COL1A1, CHAD, SGCA | de novo | pathogenic | – |
| 2 | M-6 | >30 1 | PCDH11X | maternal | pathogenic | chromosome Xp11.23-11.22 duplication syndrome |
| 3 | M-1 | 10 | TPPP, TERT, NDUF6, SRD5A1, SEMA5A, MARCH6, CTNND2, DNAH5 | de novo | pathogenic | chromosome 5p deletion syndrome (Cri-du-Chat syndrome) |
| 4 | M-6 | >30 | KCNQ3 | de novo | pathogenic | – |
| 5 | F-5 | >30 >30 | FBX0025, TNKS, MSRA, MIR124-1, CLN8, DLGAP2 SMARCA2 | paternal balanced reciprocal translocation | pathogenic | – |
| 6 | F-3 | 3 | PLGLA, RGPD3, ST6GAL2 | de novo | VUS, likely pathogenic | – |
| 7 | F-3 | >30 | NAA15, UCP1, MAB21L2, GRIA2, TLL1, VEGFC | de novo | VUS, likely pathogenic | – |
| 8 | F-1 | 27 | ZNF141, PIGG, PDE6B, CPLX1, IDUA, RNF212, UVSSA, FGFR3 | de novo | pathogenic | chromosome 4p16.3 deletion syndrome (Wolf-Hirschhorn syndrome) |
| 9 | F-4 | >30 | TUPLE1, TBX2, COMT, CRKL | maternal | pathogenic | chromosome 11q11.2 deletion syndrome (DiGeorge syndrome) |
| 10 | M-1 | 13 >30 | CNTN6, CHL1 LITRK3, SERPINI1, PDCD10, NAALA, DL2NGLN1, E1F2B5, ALG3 | paternal inv(3)(p25q25) | pathogenic | 3p syndrome 3q26 microduplication syndrome |
| 11 | F-1 | 12 | OTUD7A, CHRNA7 | de novo | pathogenic | chromosome 15q13.3 deletion syndrome |
| 12 | F-4 | 18 | NUS1, SLC35F1 | de novo | pathogenic | – |
| 13 | F-1 | 3 | AMELX, MSL3 | de novo | VUS, no sub-classification | – |
| 14 | M-10 | 17 | – | de novo | benign | – |
| 15 | M-3 | 1 | DOCK8 | de novo | benign | – |
| 16 | F-10 | 3 | METLLP, IGSF6, OTOA | de novo | benign | – |
| 17 | F-8 | 4 | GUF1, GNPDA2 | de novo | VUS, no subclassification | – |
| 18 | F-10 | >30 | FANCB, PIGA, AP1S2, NHS, CDKL5, PDHA1, PHEX, SMPX, CNKSR2, RPS6KA3, ARX | de novo | pathogenic | – |
| 19 | M-6 | >30 | SHOX, CSF2RA, USP9Y, NLGN4Y | de novo | VUS, likely benign | – |
| 20 | F-7 | 0 | – | maternal | benign | – |
| 21 | M-4 | 2 | ABCC6 | de novo | VUS, no subclassification | – |
| 22 | F-3 | 0 | – | paternal | benign | – |
| 23 | F-2 | 4 | – | maternal | benign | – |
| 24 | F-1 | 211 | CTCF, MAF, GNAO1 | de novo | pathogenic | – |
| 25 | F-2 | 1 | FHIT | de novo | VUS, likely pathogenic | – |
| 26 | F-14 | >30 | GFRA2, DOK2, XPO7, FGF17 | de novo | VUS, likely pathogenic | – |
| 27 | M-12 | 2 | OTUD7A, CHRNA7 | paternal | pathogenic | chromosome 15q13.3 duplication syndrome |
| 28 | M-3 | 12 | NDE1, NOMO1, NPIPA1, PDXDC1, NTAN1, RRN3, MARF1, MYH11, FOPNL, ABCC1, ABCC6, NOMO3 | de novo | pathogenic | – |
| 29 | F-7 | >30 | DLK1, MIR134, MIR541, CCDC85C, EVL, YY1, BEGAIN | de novo | pathogenic | – |
| 30 | F-4 | 29 | PTPRA, GNRH2, MRPS26, OXT, AVP, LZTS3, ITPA, SLC4111, ATRN, ADAM33, SIGLEC1, HSPA12B | de novo | VUS, no subclassification | – |
| 31 | M-14 | >30 | PIAS4, ATCAY, EEF2, MAP2K2 | de novo | pathogenic | – |
| 32 | M-25 | 19 | MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3, GABRA5, GABRG3, OCA2, HERC2 | de novo | pathogenic | chromosome 15q11-q13 duplication syndrome |
| 33 | F-4 | 4 | VEGFC, NEIL3, AGA, AGU | de novo | VUS, likely pathogenic | – |
| 34 | M-14 | 19 | ZMYND11 | de novo | pathogenic | – |
| 35 | M-12 | >30 | RAPGEF4, DLX1, DLX2, CHN1, SP3, HOXD cluster | de novo | pathogenic | – |
[i] #: patient number; aCGH: array-based comparative genomic hybridization; M: male; F: female; DD: developmental delay; IUGR: intrauterine growth retardation; VSD: ventricular septal defect; VUS: uncertain clinical significance; DD/ID: developmental delay/intellectual disability; EEG: electroencephalogram; ASD: autism spectrum disorder; ADHD: attention deficit hyperactivity disorder.
Table 2
Detailed neurological findings of the patients.
| # | Sex-Age | Epilepsy | Electroencephalogram | Brain Magnetic Resonance Imaging | Anti Epileptic Therapy Response |
|---|---|---|---|---|---|
| 1 | M-4 | – | normal | normal | – |
| 2 | M-6 | focal temporal lobe epilepsy started at the age of 5 months | left temporal discharges | left temporal uncal dysplasia | seizures controlled with the use of multi anti epileptic drugs |
| 3 | M-1 | – | slowing of background activity | midbrain and pontine hypoplasia with enlargement of lateral ventricles | – |
| 4 | M-6 | absence of seizures at the of 3 years | generalized SWDs maximally located at the post regions triggered with hyperventilation | normal | seizures controlled with the use of multi anti epileptic drugs |
| 5 | F-5 | head drop seizures started at the age of 3 years | SWDs located on bilateral central regions | normal | seizures controlled with the use of multi anti epileptic drugs |
| 6 | F-3 | focal motor seizures started at the age of 5 months | SWDs located on cetro-temporal regions | normal | seizures controlled with the use of multi anti epileptic drugs |
| 7 | F-3 | focal motor seizures started at the age of 3 months | SWDs located on frontotemporal discharge | normal | seizures controlled with the use of multi anti epileptic drugs |
| 8 | F-1 | focal motor seizures started at the age of 5 months | multifocal epileptic discharges with normal background activity | normal | seizures controlled with the use of multi anti epileptic drugs |
| 9 | F-4 | – | normal | normal | – |
| 10 | M-1 | focal motor seizures started at the age of 7 months | SWDs located on frontotemporal discharge | normal | seizures controlled with the use of multi anti epileptic drugs |
| 11 | F-1 | – | normal | normal | – |
| 12 | F-4 | myoclonic asthatic seizures started at the age of 3 years | 3.0–3.5 hz generalized SWDs | normal | seizures controlled with the use of multi anti epileptic drugs |
| 13 | F-1 | – | difuse slowing of the background activity without epileptic activity | cerebral and white matter atrophy | – |
| 14 | M-10 | migratuar clonic seizures started as newborn | hypsarrhythmia | cerebral and white matter atrophy with enlargement of lateral ventricles | seizures controlled with the use of multi anti epileptic drugs |
| 15 | M-3 | – | normal | normal | – |
| 16 | F-10 | – | difuse slowing of the background activity without epileptic activity | cerebral and white matter atrophy with enlargement of lateral ventricles | – |
| 17 | F-8 | focal hypomotor seizures started at the age of 5 months | SWDs located on temporoparietal and occipital regions | cerebral and white matter atrophy with enlargment of lateral ventricle and hydrocephalus | seizures controlled with the use of multi anti epileptic drugs |
| 18 | F-10 | absence seizures started at the age of 4 years | 3.0–3.5 hz generalized SWDs | normal | seizures controlled with the use of multi anti epileptic drugs |
| 19 | M-6 | secondary generalized seizures and status epilepticus started at the age of 6 months | multifocal epileptic discharges with normal background activity | normal | seizures controlled with the use of multi anti epileptic drugs |
| 20 | F-7 | multiple types of seizures started at the age of 18 months | multifocal epileptic discharges with slowing of background activity | Type 1 tip1 pachygyria, lis-sencephaly, nodular heterotropy | seizures were resistant to anti epileptic therapy |
| 21 | M-4 | infantile spasm seizures started at the age of 4 months | hypsarrythmia | bilateral gliosis on the occipital regions | seizures were controlled with ACTH therapy |
| 22 | F-3 | – | normal | normal | – |
| 23 | F-2 | infantile spasm seizures started at the age of 4 months | multifocal epileptic discharges with slowing of background activity | bilateral gliosis on the occipital regions and enlargement of lateral ventricles | seizures were resistant to anti epileptic therapy |
| 24 | F-1 | – | normal | normal | – |
| 25 | F-2 | – | normal | normal | – |
| 26 | F-14 | – | normal | normal | – |
| 27 | M-12 | – | normal | normal | – |
| 28 | M-3 | febrile seizures started at the age of 12 months and restarted at the age of 2 years | normal | normal | seizures were controlled with the use of a single anti epileptic drug |
| 29 | F-7 | – | normal | normal | – |
| 30 | F-4 | myoclonic seizures started at the age of 18 months | generalized polyspike waves | normal | seizures were controlled with the use of multi anti epileptic drug |
| 31 | M-14 | – | normal | normal | – |
| 32 | M-25 | – | normal | normal | – |
| 33 | F-4 | generalized polyspike waves | normal | seizures were controlled with ACTH therapy | |
| 34 | M-14 | – | normal | normal | – |
| 35 | M-12 | – | normal | cerebral atrophy | – |
[i] #: patient number; M: male; F: female; EEG: electroencephalogram; MRI: magnetic resonance imaging; SWDs: sleep-wake disturbances, ACTH: adrenocorticotropic hormone.