Table 2.
Summary of genes associated with NDDs, and studies conducted in zebrafish and mouse models
| Zebrafish | Human | Mouse | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Gene symbol | Previous study | This F0 study | Gene symbol | Inheritance, Phenotype MIM # | Common phenotypes in patients (PMID) | Gene symbol | Phenotypes in mouse knockout (PMID) | ||
| mRNA expression (ZFIN or PMID) | Tool | Results (PMID) | Phenotypes | ||||||
| atad3 | Brain, eye, otic vesicle, liver, intestine, skeletal muscles, and pronephric ducts (This study) | – | – | Small brain and eyes. No swim bladder. Heart edema. Reduced VSR and AEBR. Increased Oil Red O staining. Aberrant craniofacial feature. Decrease locomotor activity upon LDT. | ATAD3A | AD/AR, (617183) AR, (618810) | Axonal neuropathy, optic atrophy or cataracts, seizures, cerebellar atrophy, and hypertrophic cardiomyopathy (28158749); Fatal congenital pontocerebellar hypoplasia (28549128); Hearing loss (28549128); non-alcoholic fatty liver disease (35513069); facial dysmorphism (29053797). | Atad3a | Growth retardation, embryos die around embryonic day E7.5. (23372768) |
| afg2b (spata5l1) | Brain ventricles, eye, and otic vesicle (This study) | – | – | Small brain and eyes. No swim bladder. Heart edema. Reduced VSR and AEBR. Increase locomotor activity upon LDT. | AFG2B (SPATA5L1) | AR (619615, 619616) | Deafness, autosomal recessive 119; NDD with hearing loss and spasticity. Microcephaly, epilepsy, visual impairment, and hearing loss. (34626583) | Afg2b (Spata5l1) | Embryonic lethal in homozygous. (IMPC) |
| cox4i1 | Brain, eye, liver, skeletal, muscles, and intestine (ZFIN) | – | – | Small brain and eyes. No swim bladder. Heart edema. Short stature. Reduced VSR and AEBR. Decrease locomotor activity upon LDT. | COX4I1 | AR (619060) | Mitochondrial complex IV deficiency, nuclear type 16. Microcephaly, short stature, developmental delay, visual problem, etc. Leigh syndrome phenotype. (31290619) | Cox4i1 | Homozygous: embryonic lethal. Heterozygous: abnormal embryo size, abnormal brain development. (IMPC) |
| cachd1 | Brain, eye, otic vesicles, and spinal cord (This study) | CRISPR/ Cas9 | Homozygous mutant show craniofacial defect. (38158856) | Craniofacial defect. No swim bladder. Normal VSR. Small otoliths and reduced AEBR. Normal locomotor activity upon LDT. | CACHD1 | AR (620144) | Rare neurodevelopmental syndrome characterized by variable developmental delay, cognitive impairment and craniofacial dysmorphism. (38158856) | Cachd1 | Loss-of-function mutations have otoconia deficiencies, hearing and balance impairment. (34388681) |
| necap1 | Brain, eye, otic vesicles, and spinal cord (This study) | – | – | No obvious morphological abnormality. Reduced VSR and AEBR. Small otoliths. Normal locomotor activity upon LDT. | NECAP1 | AR (615833) | Developmental and epileptic encephalopathy 21 | Necap1 | Embryonic lethal in homozygous. (IMPC) Giant Schnauzer dogs carry homozygous single nucleotide variant display progressive retinal atrophy. (31117272) |
| sd ha | Brain, eye, liver and skeletal muscles (ZFIN) | – | – | Small brain and eyes. No swim bladder. Reduced VSR and AEBR. Decrease locomotor activity upon LDT. | SD HA | AR (613642, 252011), AD (619259, 614165) | Cardiomyopathy, dilated, 1GG; Mitochondrial complex II deficiency, nuclear type 1 (Leigh syndrome); Neurodegeneration with ataxia and late-onset optic atrophy; Pheochromocytoma/paraganglioma syndrome 5. | Sd ha | Embryonic lethal in homozygous. (IMPC) |
| cog1 | Brain ventricles and otic vesicle (This study) | – | – | Aberrant craniofacial features. Small head and eye. Reduced VSR and AEBR. Normal locomotor activity upon LDT. | COG1 | AR (611209) | Congenital disorder of glycosylation, type Iig. Microcephaly, facial dysmorphism, hearing loss, etc. (19008299) | Cog1 | Embryonic lethal in homozygous. (IMPC) |
| yif1b | Whole organism (ZFIN) | – | – | No obvious morphological abnormality. Reduced VSR. Normal AEBR. Normal locomotor activity upon LDT. | YIF1 B | AR (619125) | Kaya–Barakat–Masson syndrome and Visual impairment. (32006098, 33103737 and 34373908) | Yif1b | Knockout mice did not show spontaneous seizures or increased susceptibility to seizures, although mutant mice showed impaired visual perception. Basal locomotion was normal. (33103737) |
| atn1 | – | – | – | No obvious morphological abnormality. Reduced VSR and AEBR. Normal locomotor activity upon LDT. | ATN1 | AD (618494, 125370) | Congenital hypotonia, epilepsy, developmental delay, and digital anomalies. Dentatorubral-pallidoluysian atrophy. Visual and hearing impairments. (34212383, 36007104) | Atn1 | Homozygous knockout mice are indistinguishable from WT mice. (17150957) |
| itsn1 | Brain, eye, ear, and skeletal muscle (This study) | – | – | No obvious morphological abnormality. Reduced VSR. Normal AEBR. Decrease locomotor activity upon LDT. | ITSN1 | NA | Autism spectrum disorders, intellectual disability and epilepsy. (34707297) | Itsn1 | Homozygous knockout mice display impaired spatial learning and memory. (23447614) |
| mdh2 | Brain, eye, and skeletal muscle (ZFIN) | – | – | No obvious morphological abnormality. Reduced VSR and AEBR. Decrease locomotor activity upon LDT. | MDH2 | AR (617339) | Developmental and epileptic encephalopathy 51.Early-onset generalized hypotonia, psychomotor delay, refractory epilepsy (34766628). Vision impairment (36420423). | Mdh2 | Embryonic lethal in homozygous (IMPC). |
| lonp1 | Brain, eye, otic vesicle, liver, intestine, and skeletal muscles (This study) | – | – | No obvious morphological abnormality. Normal VSR. Reduced AEBR. Normal locomotor activity upon LDT. | LONP1 | AR (600373) | Cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome. Developmental delay, craniofacial anomalies, cataracts, hearing loss, short stature, etc. (25574826) | Lonp1 | Embryonic lethal in homozygous. (25017063) |
| slc25a4 | Skeletal muscles (ZFIN) | – | – | No obvious morphological abnormality. Normal VSR and AEBR. Normal locomotor activity upon LDT. | SLC25A4 | AD (617184), AR (615418) | Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type); Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type). | Slc25a4 | Dilated cardiomyopathy. (21232697) |
| tpm1 | Heart and skeletal muscles (ZFIN) | – | – | Small brain and eyes. No swim bladder. Reduced VSR and AEBR. | TPM1 | AD (611878, 115196) | Cardiomyopathy, dilated, 1Y; Cardiomyopathy, hypertrophic, 3. Atrial septal defect (35243414). | Tpm1 | Early embryonic lethality of homozygous knockout mouse embryos. (24500875) |
| qsox1 | Brain, liver, otic vesicle, and pronephric duct (ZFIN) | – | – | No obvious morphological abnormality. Normal VSR and AEBR. Decrease locomotor activity upon LDT. | QSOX1 | NA | – | Qsox1 | Homozygous knockouts are viable but exhibit moderate dilated cardiomyophathy. (29723491) |
| ndufa12 | Whole organism (This study) | – | – | No obvious morphological abnormality. Reduced VSR and AEBR. Normal locomotor activity upon LDT. | NDUFA12 | AR (618244) | Mitochondrial complex I deficiency nuclear type 23, including visual impairment and movement disorders. (35141356) | Ndufa12 | – |
| phf8 | Brain and jaw (20622853); ear and neuromast (33330448) | Morpholino | Brain apoptosis and craniofacial defect (20622853). | No obvious morphological abnormality. Normal VSR and AEBR. Normal locomotor activity upon LDT. | PHF8 | XLR (300263) | Intellectual developmental disorder, X-linked, syndromic, and Siderius type. Bilateral or unilateral cleft lip/cleft palate. (17661819) | Phf8 | No obvious developmental defects, no cognitive impairment. With stress-induced anxiety- and depression-like behaviour. (28485378) |
| aifm1 | Brain, eye, liver, and skeletal muscles (ZFIN) | – | – | No obvious morphological abnormality. Reduced VSR and AEBR. Normal locomotor activity upon LDT. | AIFM1 | XLR (300816, 310490, 300614, 300232) | Combined oxidative phosphorylation deficiency 6; Cowchock syndrome; Deafness, X-linked 5; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy. | Aifm1 | Homozygous knockout mice exhibit smaller body size and reduced forebrain. (16788063) |
| kdm3b | Whole organism (ZFIN) | – | – | No obvious morphological abnormality. Reduced VSR and AEBR. Small otoliths. Decrease locomotor activity upon LDT. | KDM3B | AD (618846) | Diets-Jongmans syndrome. Behavioral problems, including ADHD and autism. Hearing loss and low vision. (30929739) | Kdm3b | Knockout mice showed restricted postnatal growth and female infertility. (25892958) |
| thbs1b | Brian, head mesenchyme, eye, otic vesicle, and muscle pioneer (ZFIN) | – | – | No obvious morphological abnormality. Normal VSR and AEBR. Normal locomotor activity upon LDT. | THBS1 | NA | – | Thbs1 | Homozygous knockout mice are viable, fertile, and healthy except for lung inflammation and an increase in the number of circulating white blood cells. (9486968) |
The mRNA expression patterns for each genes were obtained from published studies (PubMed ID), ZFIN, or this study. The gross morphological phenotypes were determined by observation or measurement after imaging (e.g. Fig. 8E–J, Supplementary Fig. S16F–Y, and Supplementary Fig. S17A and B). The behaviors were summarized from Fig. 8L–N and 8P, Supplementary Fig. S17C and D, and Supplementary Figs S18–S20.
Abbreviations: LDT: light-dark transitions; AR: autosomal recessive; AD: autosomal dominant; NA: not available; VSR: visual startle response; AEBR: acoustic evoked behavioral response; IMPC: International Mouse Phenotyping Consortium; ZFIN: Zebrafish Information Network (https://zfin.org/).