Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. The RORB Gene
3.2. The PRR12 Gene
3.3. The SATB1 Gene
3.4. RFX Family Genes
3.5. The GRIA2 Gene
3.6. The TAOK1 Gene
4. Concluding Remarks and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Online Resources
References
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Novel Gene | Category | Specific and Commonly Reported Clinical Features |
---|---|---|
SRPR | Other | _ |
RORB | Gene expression regulation | Epilepsy |
DPYSL2 | Cytoskeleton | - |
AP2S1 | Neuronal communication | - |
MKX | Gene expression regulation | - |
MAP1A | Cytoskeleton | - |
CELF4 | Gene expression regulation | - |
PHF12 | Gene expression regulation | - |
TM9SF4 | Other | - |
PRR12 | Neuronal communication | Variable structural eye defects |
LDB1 | Gene expression regulation | - |
EIF3G | Gene expression regulation | - |
KIAA0232 | Other | - |
VEZF1 | Gene expression regulation | - |
ZMYND8 | Gene expression regulation | - |
SATB1 | Gene expression regulation | Severe ID and epilepsy (patients with missense variants), eye and dental anomalies |
RFX3 | Gene expression regulation | Distinct behavioral issues |
PPP5C | Other | |
TRIM23 | Other | |
ELAVL3 | Gene expression regulation | |
GRIA2 | Neuronal communication | Rett-like features/hyperventilation |
LRRC4C | Neuronal communication | |
NUP155 | Other | |
PPP1R9B | Neuronal communication | |
HDLBP | Gene expression regulation | |
TAOK1 | Cytoskeleton | Infant difficulties in feeding; muscular hypotonia |
UBR1 | Other | |
TEK | Other | |
CORO1A | Cytoskeleton | |
HECTD4 | Other | |
NCOA1 | Gene expression regulation |
Gene | Functional Role | New Evidence (Ref) | Number of Patients | Gene Variant | Origin | Associated Phenotype |
---|---|---|---|---|---|---|
RORB | Gene expression regulation | [2] | One patient | SNV, not specified | de novo | Eyelid myoclonia with absences, intellectual disability and ADHD |
[3] | Fourteen individuals (12 affected) Belonging to four families | c.111C>G p.Ser37Arg c.777G>T p.Trp259Cys c.96_237del141p.Gly32_Ala79del48 c.1162A>T p.Ile388Phe | inherited | Generalized and occipital epilepsy with or without ID/learning difficulties; ID only also reported | ||
[4] | One individual | CNV, dupl chr9:123.881.988-123.980.981 | de novo | Severe ASD (non verbal, ID, and stereotypes) | ||
PRR12 | Neuronal communication | [5] | Twenty-four individuals | Twelve frameshift, six nonsense, one splice, two missense, and one gross deletion (see the manuscript for full description of variants) | de novo | Neurodevelopmental impairment (100%), variable structural eye defects (50% patients), hypotonia (61%), heart defects (52%), growth failure (54%), kidney abnormalities (35%) |
[6] | Five individuals | c.5624-2A>G p.Asp1875Glyfs*54 c.4502_4505delTGCC p.Asp1501Argfs*146 c.2353_2360delGCCGGGGG p.Ala785Profs*2 c.2045delG p. p.Gly682Aspfs*44 c.1918G>T p.Glu640* c.677dupC p.Tyr227Leufs*41 c.903_909dup p.Pro304Thrfs*46 | de novo and inherited | Unilateral or bilateral microphtalmia (100%), delay (60%), short stature (40%), dysmorphic facies (40%) | ||
SATB1 | Gene expression regulation | [7] | Forty-two individuals | Thirty missense variants and ten protein-truncating variants (two nonsense, seven frameshift, and one splice) | de novo and inherited | Two clinically different NDDs: missense variants were associated with a more severe phenotype than PTVs. Subjects carrying missense variants had severe ID (57%); spasticity, hypotonia, and epilepsy were more common in subjects with missense variants. Dysmorphic features were also different between the two NDD groups. Commonly reported anomalies: eye and dental abnormalities, dysmorphic facial features |
RFX gene family | Gene expression regulation | [8] | Fifteen individuals with RFX3 variants | Two frameshift variants, two splice donor variants, eight missense variants, one in-frame deletion, one 42 Kb deletion involving the last two exons of RFX3, and one 227 Kb deletion involving only RFX3 | de novo (14) and inherited (1) | 100% developmental delay: 72% ASD and ID of varying severity or global developmental delay in young children (78%) and ADHD (56%). Distinct behavioral features in most individuals (87%): easy excitability/overstimulation, hypersensitivity to sensory stimuli (particulary auditory), anxiety, emotional dysregulation, and/or aggression. Sleep difficulties (44%). Seizures (17%). |
Four individuals with RFX4 variants | One in-frame deletion, two missense variants, one missense variant (recessive, homozygous) | de novo (3) and inherited (1 recessive) | 100% had ID or global developmental delay; 83% ASD. Seizures (33%) | |||
Fourteen individuals with RFX7 variants | Four frameshift variants, give stop-gain variants, one in-frame deletions, two missense variants | de novo | 100% language delay; most (93%) had ID/global developmental delay; ASD (36%); ADHD (29%); in most individuals, behavioral features similar to those observed for RFX3 individuals | |||
GRIA2 | Neuronal communication | [9] | One girl | c.1522G>T (p.Glu508Ter) | de novo | Childhood onset schizophrenia, obsessive–compulsive disorder, anxiety, and aggressive behavior |
[10] | Twenty-eight patients | -SNVs: 18 missense, 2 splice site, 1 in-frame deletion, 1 stop-gain, and 2 frameshift -three 4q32.1 microdeletions | de novo | ID, ASD, developmental delay, language impairment and striking neurological features including epilepsy or developmental epileptic encephalopathy and Rett-syndrome-like anomalies (hand washing stereotypes, regression) gait abnormalities including ataxia and dyspraxia, abnormal sleep rhythm, and irregular breathing patterns with hyperventilation episodes | ||
TOAK1 | cyotoskeleton | [11] | Eight patients | Four missense (p.Glu17Gly, p.Lys298Glu, p.Asp305Ala, p.Ser111Phe), three nonsense (p.Glu781*, p.Gln544*, p.Glu830*) and one frameshift variants (p.Leu790Phefs*3) | de novo | Broad neurodevelopmental spectrum: developmental delay (100% individuals with speech/language or motor delay), ID (50% individuals), muscular hypotonia (75% individuals), facial dysmorphisms (63%) |
[12] | Twenty-three patients | -SNVs: five missense (p.Leu548Pro, p.Arg150Ile, p.Leu167Arg, p.Leu315Phe, p.Met231Val), seven nonsense (p.Gln607*, p.Lys277*, p.Glu220*, p.Arg709*, p.Arg695*, p.Arg702*, p.Arg605*), four indels (two of unknown effects on the protein, p.Lys429Asnfs*42, p.Lys78Valfs*20) and three splice site -CNVs: four microdeletions (size range: 807 bp–2 Mb) | de novo (17), inherited (3), unknown (3) | ID/DD and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems. Common facial features include frontal bossing, downslanting palpebral fissures, long philtrum, and bulbous nasal tip |
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Lintas, C.; Sacco, R.; Azzarà, A.; Cassano, I.; Gurrieri, F. Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results. J. Clin. Med. 2021, 10, 5060. https://doi.org/10.3390/jcm10215060
Lintas C, Sacco R, Azzarà A, Cassano I, Gurrieri F. Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results. Journal of Clinical Medicine. 2021; 10(21):5060. https://doi.org/10.3390/jcm10215060
Chicago/Turabian StyleLintas, Carla, Roberto Sacco, Alessia Azzarà, Ilaria Cassano, and Fiorella Gurrieri. 2021. "Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results" Journal of Clinical Medicine 10, no. 21: 5060. https://doi.org/10.3390/jcm10215060
APA StyleLintas, C., Sacco, R., Azzarà, A., Cassano, I., & Gurrieri, F. (2021). Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results. Journal of Clinical Medicine, 10(21), 5060. https://doi.org/10.3390/jcm10215060