Table 2 Summary of main clinical features and genetic findings in patients with P/LP or high-level candidate variants
From: Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly
Patients with P/LP findings in established disease genes | ||||||||
|---|---|---|---|---|---|---|---|---|
No. | Patient ID | Agea | Microcephaly subgroup | Main clinical feature | Cerebral MRI finding | Genetic finding | Disorder | Function/pathway |
1 | 59571 | 10.9 | PM | Moderate global DD, moderate–severe ID, muscular hypotonia, myopia, short stature, scoliosis | Abnormal gyrus, corpus callosum dysgenesis, everted hippocampi | CDK5RAP2: c.[4546G>T];[3928G>T], p.[(Glu1516*)];[(Glu1310*)], AR (CH) | MCPH3 (MIM 604804) | Centrosome, spindle and microtubule organization |
2 | 73869 | 8.8 | PM | Mild motor DD, moderate speech delay, moderate ID, mild feeding difficulties, cryptorchidism | Dysmorphic corpus callosum with absence of the splenium, hypoplasia of frontal horns of lateral ventricles | CDK5RAP2: c.[558_559del];[4441C>T], p.[(Glu186Aspfs*32)];[(Arg1481*)], AR (CH) | MCPH3 (MIM 604804) | Centrosome, spindle and microtubule organization |
3 | 74812 | Aborted at 23 GW | PM | Autopsy: 2-lobed right lung and accessory spleen | Autopsy: Absence of corpus callosum | PLK4: c.[1111C>T];[881T>G], p.[(Arg371*)];[(Ile294Ser)], AR (CH) | PLK4-related disorder (MIM 616171) | Centriole duplication |
4 | 77804 | 0.8 | PM | Moderate global DD, movement disorder | Simplified cortical gyri and dysgenesis of corpus callosum, larger cerebellum and brain stem relative to the supratentorial region | PLK4: c.[212C>T];[760_761insAC], p.[(Ser71Phe)];[(Leu254Tyrfs*2)], AR (CH) | PLK4-related disorder (MIM: 616171) | Centriole duplication |
5 | 68978 | 2.1 | PM | Severe global DD, seizure | Microlissencephaly with simplified cortical pattern | ASPM: c.[3796G>T];[3796G>T], p.[(Glu1266*)];[(Glu1266*)], AR (Homo) | MCPH5 (MIM 608716) | Spindle organization and orientation |
6 | 57602 | 3.8 | PM | Severe global DD, spastic hemiparesis, patent ductus arteriosus, vesicoureteral reflux | Simplified gyral pattern, polymicrogyria, schizencephaly | DHTKD1: c.[2185G>A];[2185G>A], p.[(Gly729Arg)];[(Gly729Arg)], AR (Homo) | 2-aminoadipic 2-oxoadipic aciduria (MIM 204750) | Amino acid degradation, mitochondrial biogenesis |
7 | 75955 | 3 | PM | Severe global DD, decreased reflexes, severe failure to thrive, congenital cataract, hepatomegaly, micropenis | Hypomyelination, thin corpus callosum | ERCC6: c.[850G>T];[850G>T], p.[(Glu284*)];[(Glu284*)], AR (Homo) | Cockayne syndrome (MIM 133540) | DNA repair |
8 | 75892 | 2 | PM | Moderate to severe global DD, stereotypy, happy demeanor, truncal obesity | Mild cortical atrophy, delayed myelination | TRAPPC9: c.[3214C>T];[3214C>T], p.[(Arg1072*)];[(Arg1072*)], AR (Homo) | Autosomal recessive mental retardation 13 (MIM 613192) | Neuronal NF-kappa-B signaling |
9 | 53792 | 8.3 | PM | Mild global DD, mild ID, hypotonia, seizures, failure to thrive, short stature, uvula bifida, mild truncal adiposity | No abnormality in cerebral MRI | TRMT10A: c.[379C>T];[379C>T], p.[(Arg127*)];[(Arg127*)], AR (Homo) | TRMT10A-related disorder (MIM 616033) | Transcriptional regulation |
10 | 74601 | 2.3 | PM | Severe global DD, cerebral movement disorder, craniosynostosis, delayed visual maturation, strabismus, hyperopia, astigmatism, torticollis, atrial septal defect | Right and left plagiocephalus | 1.48-Mb dup in chr2:96732519-98212850, DN | 2q11.2 duplication (Riley et al.38) | – |
KAT6A: c.3555_3556insA, p.(Ala1186Serfs*5), DN | Autosomal dominant mental retardation 32 (MIM 616268) | Transcriptional regulation | ||||||
11 | 74444 | 4.5 | PM | Mild global DD, muscular hypotonia, epilepsy, left central cataract, left chorioretinal coloboma, left strabismus and nystagmus | Multiple subependymal heterotopia in lateral ventricles | 2-Mb del in chr1: 145940520-147922681, DN | Chromosome 1q21.1 deletion syndrome (MIM 612474) | – |
12 | 74579 | 2.2 | PM | Mild global DD, generalized hypotonia, bilateral cleft lip and cleft palate, recurrent obstipation | N/A | 7.1-Mb del in chr1:172427631-179864641, DN | 1q24q25 deletion (Chatron et al.39) | – |
13 | 70547 | 7.1 | PM | Moderate speech delay, moderate–severe ID, concentration deficit, EEG abnormalities, mitral valve prolapse, cyanotic episode, contractures, hip dysplasia | Enlarged subarachnoidal space | HDAC8: c.522C>A, p.(Tyr174*), DN | Cornelia de Lange syndrome 5 (MIM 300882) | Transcriptional regulation |
14 | 32410 | 15.3 | PM | Moderate global DD, moderate ID, bilateral hearing loss, severe progressive optic atrophy, moderate hyperopia, distal spasticity, neurogenic clubfeet, growth deficiency, steroid-resistant focal segmental glomerulosclerosis | Cerebellar hypoplasia, bilateral atrophy of optical nerves | MT-ATP6: m.9185T>C, p.(Leu220Pro), DN | MT-ATP6-related mitochondriopathy | ATP synthesis |
15 | 70688 | 1.6 | PM | Moderate global DD, high palate, inguinal hernia, bilateral undescended testes, sacral dimple | Abnormal signal intensity in the posterior horns of lateral ventricles, prominent Robin–Virchow area | 736 Kb dup in chrX:53480222-54215972, and 660 Kb dup in chr16:29580020-30240227, XLR | Chromosomes Xp11.22 and 16p11.2 microduplication syndromes (MIM 300705 and 614671) | – |
16 | 75473 | 2.5 | PM | Severe global DD, 2 episodes of seizure | Hypoplasia of cerebellar vermis | SLC9A6: c.[615_616insT];[0], p.[(Arg206Serfs*58)];[0], XLR | Christianson syndrome (MIM 300243) | Endosome regulation |
17 | 72526 | 2.8 | SM | Mild–moderate global DD, brachycephaly, plagiocephaly, atactic gait, seizures, mild thrombopenia, discrete microcytic anemia | Simplified gyri, slight ventricular dilatation, slightly flattened nucleus caudatus and small pituitary gland | DYRK1A: c.665-4del, r.665_951del, p.(Ile222Aspfs*22), DN | Autosomal dominant mental retardation 7 (MIM 614104) | Neuronal proliferation, differentiation, plasticity and death |
18 | 59484 | 8 | SM | Severe global DD, severe ID, hypotonia, coordination problem, epilepsy, strabismus convergence, uvula bifida, growth deficiency | No abnormality in cerebral MRI | FBXO11: c.1868C>G, p.(Thr623Arg) (Gregor et al.35), DN | FBXO11-related disorder (MIM 618089) | Protein ubiquitination |
19 | 57570 | 3.5 | SM | Severe global DD, muscular hypotonia, growth deficiency, complex pulmonary atresia with ventricular septal defect, immune deficiency (T-cell lymphopenia), left vesicoureteral reflux | N/A | KMT2A: c.8724del, p.(Glu2908Aspfs*21), DN | Wiedemann–Steiner syndrome (MIM 605130) | Transcriptional regulation |
20 | 72938 | 2.9 | SM | Severe global DD, cyanotic seizures, pain insensitivity, sterotypic movements, inappropriate laughter, tonus dysregulation, cataract, dysphagia | Delayed myelination | NACC1: c.892C>T, p.(Arg298Trp), DN | NACC1-related disorder (MIM 617393) | Transcriptional regulation |
21 | 69444 | 0.8 | SM | DD, muscular hypotonia | No abnormality in cerebral MRI | POGZ: c.1580A>G, p.(Asp527Gly), DN | White–Sutton syndrome (MIM 616364) | Mitotic progression |
22 | 73824 | 0.9 | SM | Mild–moderate motor DD, mild speech delay, hypotonia, seizures, pulmonary stenosis | No abnormality in cerebral MRI | PTPN11: c.923A>G, p.(Asn308Ser), DN | Noonan syndrome (MIM 163950) | Cell growth, differentiation, mitotic cycle |
23 | 67093 | 5.8 | SM | Moderate global DD, muscular hypotonia, behavior abnormality, feeding difficulties, recurrent subfebrile temperature, left iris coloboma | N/A | TLK2: c.968+2T>G, p.?, DN | Autosomal dominant mental retardation 57 (MIM 618050) | DNA repair |
24 | 74956 | 2.7 | SM | Mild–moderate DD, muscular hypotonia, strabismus (Duane syndrome), short stature, vesicoureteral reflux due to renal tubular ectasia, joint laxity, chronic obstipation | Partial agenesis of the corpus callosum | 509 Kb del in chr17:43703801-44212416, assumed DN (absent in mother) | Koolen–de Vries syndrome (MIM 610443) | – |
25 | 76870 | 16.2 | Unknown onset | Moderate–severe global DD, moderate–severe ID, epilepsy, behavior abnormalities, hearing loss, retinal dystrophy, abnormality of dental enamel, recurrent infections | N/A | KARS: c.[1772A>T];[1772A>T], p.[(Asn591Ile)];[(Asn591Ile)], AR (Homo) | Autosomal recessive deafness 89 (MIM 613916) | Protein translation |
26 | 45969 | 15.3 | Unknown onset | Severe global DD, severe ID, epilepsy, ataxic movement disorder, stereotypy, sleep disturbances, intermittent hyperventilation, impulsivity, scoliosis | N/A | STXBP1: c.586C>T, p.(Arg122*), DN | Early infantile epileptic encephalopathy 4 (MIM 612164) | Neurotransmitter release |
27 | 55113 | 18 | Unknown onset | Learning disability (no DD), ADHD, myopia, short stature | Arachnoidal cyst | TRIO: c.4615-2del, p.?, DN | Autosomal dominant mental retardation 44 (MIM 617061) | Neuronal migration |
28 | 31773 | 17.8 | Unknown onset | Mild motor DD, moderate speech delay, mild ID, mild muscular hypotonia, ataxia, growth deficiency | N/A | 10.8-Mb del in chr7:87365891-98118059, DN | 7q21.13-q22.1 deletion (Bernardini et al.40) | – |
29 | 65891 | 12.8 | Unknown onset | Moderate–severe global DD, moderate ID, axial hypotonia, distal hypertonia (passive), spastic paraparesis, hyperactivity, sleep apnea, short stature, scoliosis, hypoplasia of the pituitary gland | N/A | MECP2: c.[1138_1144del];[0], p.[(Val380Cysfs*27)];[0], XLR | Syndromic X-linked mental retardation 13 (MIM 300055) | Transcriptional regulation |
30 | 66916 | 10.5 | Unknown onset | Fine motor problems, moderate–severe speech delay, moderate ID, dysmetria, short stature | N/A | PQBP1: c.[459_462del];[0], p.[(Arg153Serfs*41)];[0], XLR | Renpenning syndrome (MIM 309500) | Transcriptional regulation |
Patients with likely deleterious variants in high-level candidate genes | ||||||||
|---|---|---|---|---|---|---|---|---|
No. | Patient ID | Agea | Microcephaly subgroup | Main clinical feature | Cerebral MRI finding | Genetic finding | Protein | Function/pathway |
1 | 81652 | 2.3 | PM | Mild speech delay, short stature | No abnormality in cerebral MRI | SPAG5: c.[3189C>T];[1223_1224insAC], r.[3189_3198del];[=], p.[(Gly1064Glu*3)];[(Lys409Profs*19)], AR (CH) | Sperm associated antigen 5 | Centriole duplication |
2 | 68629 | 5.7 | PM | Moderate global DD, right plagiocephaly, bilateral hyperopia, short stature, congenital primary hypothyroidism (treated), bilateral cryptorchidism | No abnormality in cerebral MRI | TEDC1 (C14orf80): c.[227-5C>G];[1111del], r.[227_267del];[=], p.[(Glu76Glyfs*11)];[(Ala371Glnfs*12)], AR (CH) | Tubulin epsilon and delta complex 1 | Centriole stability |
3 | 74091 | 1.8 | PM | Severe global DD, spasticity, decreased hearing of both sides, short stature, low weight, vesicoureteral reflux | Atrophy of the white matter, a Dandy–Walker variant and a generalized hypertrophy of the cerebral and cerebellar structures, pontocerebellar hypoplasia | DDX1: c.[1333G>A];[1333G>A], p.[(Val445Ile)];[(Val445Ile)], AR (Homo) | Asp-Glu-Ala-Asp (DEAD) box helicase 1 | RNA trafficking |
4 | 75822 | 4.5 | PM | Moderate–severe global DD, hirsutism | Bilateral frontal pachygyria, delayed myelination, partial agenesis of posterior corpus callosum | VPS26A: c.[404C>T];[404C>T], p.[(Thr135Ile)];[(Thr135Ile)], AR (Homo) | VPS26, retromer complex component A | Retrograde transport of proteins from endosomes to the trans-Golgi network; Wnt signaling |
5 | 60361 | 4.8 | PM | Mild speech delay, hyperopia, left strabismus convergens, coarctation of the aorta, hypoplastic aortic arch, ventricular septal defect, atrial septal defect, bicuspid aortic valve, and persistent left superior vena cava, and ectodermal dysplasia, brachydactyly, mainly distally shortened phalanges, nail hypoplasia, lacrimal duct obstruction, oligodontia, sensitive and dry skin | N/A | ZNRF3: c.311T>C, p.(Leu104Pro), DN | Zinc and ring finger 3 | Negative regulator of the Wnt signaling pathway |
