Model: Zebrafish

Gene: RERE

Gene alteration: The genetic change responsible for the babyface (bab) phenotype was identified. there are two bab alleles; babtb210 is caused by rerea Y361X, and babtw220c is caused by rerea Y394X

Model phenotype: Both models both display nearly identical phenotypes (Schilling et al.,1996) including a small head and eyes, severely reduced pharyngeal arches and pectoral fins, and enlarged ear capsules (Fig. 1A,B).

Case# Subject 2, male, 8mo report, Hispanic

CasePresentingHPOs HP:0001276, HP:0000341, HP:0000294, HP:0000316, HP:0000286, HP:0000494, HP:0000664, HP:0008589, HP:0005989, HP:0001257 (Hypertonia, Narrow forehead, Low anterior hairline, Hypertelorism, Downslanted palpebral fissures, Epicanthus, Synophrys, Hypoplastic helices, Redundant neck skin, Spasticity)

HPOFreeText: Hypertonic(postnatal), bifrontal narrowing, low anterior hairline, mild hypertelorism, bilateral epicanthal folds, downslanted palpebral fissures, synophrys, mild hypoplastic helices, redundant nuchal skin, and spasticity of all four extremities with upper limbs being more affected than lower limbs (8 months old)

CaseNotHPOs HP:0002194, HP:0001252, HP:0012443, HP:0012372, HP:0000453, HP:0001627, HP:0000077, HP:0002650 (Gross motor delay, Hypotonia, Abnormality of the brain, Abnormal eye morphology, Choanal atresia, Congenital heart defects, Renal anomaly, Scoliosis)

CasePreviousTesting Screen for BRAF, CBL, HRAS, KRAS, MAP2K1, NRAS, PTPN11, RAF1, SCHOC2, and SOS1 was normal.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.248dup (p.Ser84ValfsTer4), de novo

ClinVar n/a

CAID CA658820860

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Subject 4, female, 17yo report, European

CasePresentingHPOs HP:0001252, HP:0001263, HP:0010864, HP:0007033, HP:0000750 (Hypotonia, Global developmental delay, Severe intellectual disability, Cerebellar dysplasia, Speech delay

HPOFreeText: hemispheric cerebellar dysplasia with abnormal lobule and fissure orientation in the inferior hemispheres(5 years); severe intellectual disability/speech delay(13 years)

CaseNotHPOs HP:0011968, HP:0012372, HP:0000453, HP:0001627, HP:0000077, HP:0002650 (Poor feeding, Abnormal eye morphology, Choanal atresia, Congenital heart defects, Renal anomaly, Scoliosis)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4303C>T(p.His1435Tyr), de novo

ClinVar n/a

CAID CA338168785

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Subject 3, male, 21yo report, European

CasePresentingHPOs HP:0030842, HP:0001631, HP:0001263, HP:0001249, HP:0001252, HP:0001251, HP:0000722, HP:0002474, HP:0001488, HP:0000565, HP:0010535, HP:0002650, HP:0002079, HP:0002363, HP:0000961, HP:0000733, HP:0002058, HP:0000490, HP:0000218, HP:0001222, HP:0001795 (Choking episodes, Atrial septal defect, Developmental delay, Intellectual disability, Hypotonia, Ataxia, OCD, Expressive language deficit, Bilateral ptosis, Esotropia, Sleep apnea, Scoliosis, Thin corpus callosum, Cyanosis, Stereotypy, Myopathic facies, Deep set eyes, High-arched palate, Spatulate thumbs, Hyperconvex nails

HPOFreeText: Choking episodes and atrial septal defect in infancy; recurrent cyanosis, mild hypotonia, ataxia, scoliosis, bilateral ptosis, esotropia, developmental delay and OCD (7 years); sleep apnea, throbbing headaches, thin corpus callosum, flattening of braistem, thin rim of sella, chronic right temporal membrane perforation and mild left sensorineural hearing loss(8 years); repetitive hand movements, limited speech, elongated/myopathic face/midfacial retraction, bilateral ptosis, deep-set eyes, high arched palate, spatulate thumbs and finger/toenail hyperconvexity(19 years).

CaseNotHPOs HP:0012372, HP:0000453, , HP:0000077 (Abnormal eye morphology, Choanal atresia, Renal anomaly)

CasePreviousTesting Reduced succinate cytochrome c reductaseactivity (19%), NADH and NADH cytochrome c activity were 40% of control.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4300T>C(p.Ser1434Pro), de novo

ClinVar n/a

CAID CA338168793

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Subject 8, male, 10yo, European

CasePresentingHPOs HP:0011968, HP:0002033, HP:0002360, HP:0002020, HP:0011848, HP:0000483, HP:0000349, HP:0000494, HP:0011230, HP:0000347, HP:0000691, HP:0003186, HP:0200055, HP:0004209, HP:0010862, HP:0000750, HP:0000729, HP:0007018, (Poor feeding, Poor suck, Difficulty sleeping, Gastroesophageal reflux, Abnormal colic, Astigmatism, Widow's peak, Downslanted palpebral fissures, Laterally extended eyebrow, Micrognathia, Microdontia, Small hands, 5th finger clinodactyly, Fine motor delay, Speech delay, Autisim spectrum disorder, ADHD

HPOFreeText: Poor latch and suck, narrow dental arches, small lower arch teeth and other phenotypes reported postnatally. Fine motor delay, speech delay, autistic spectrum, and ADHD reported at 11 months. Brain MRI normal.

CaseNotHPOs HP:0001250, HP:0001252, HP:0000708, HP:0001285, HP:0001273, HP:0006808, HP:0002334, HP:0002119, HP:0007361, HP:0025100, HP:0030301, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0000047, HP:0000028, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0004322, HP:0000256, HP:0000252, HP:0011328, HP:0002007, HP:0000325, HP:0000601, HP:0000316, HP:0000582, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000187, HP:0000218, HP:0002557, HP:0011297, HP:0001792, HP:0010490, HP:0004532, HP:0000957, (Seizures, Hypotonia, Behavioral problems, Spastic quadriparesis, Abnormal Corpus Callosum, Cerebral hypomyelination, Abnormality of cerebellar vermis, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Abnormality of the anterior commissure, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Hypospadias, Cryptorchidism, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Short stature, Macrocephaly, Microcephaly, Fontanel abnormality, Frontal bossing, Triangular face, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Broad alveolar ridges, High-arched palate, Small nipples, Digital Anomalies, Nail hypoplasia, Abnormal palmar creases, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger

Variant NM_012102.3(RERE):c.1104delA, (p.Leu369Cysfs∗16)

CAID CA658820843

gnomAD n/a

VariantEvidence n/a

CaseAddInfo No paternal DNA to prove de novo status, variant suspected to trigger NMD

CasePMIDs n/a

Case# Subject 7, male, 11yo, Dutch

CasePresentingHPOs HP:0410030, HP:0001263, HP:0001252, HP:0000494, HP:0000954, HP:0007018, HP:0001256, HP:0001273, HP:0030301, HP:0006808, HP:0011968, HP:0004322, HP:0000252 (Cleft lip, Developmental delay, Hypotonia, Down-slanting palpebral fissures, Single palmar crease, ADHD, Mild intellectual disability, Abnormal Corpus Callosum, Abnormality of the anterior commissure, Cerebral hypomyelination, Poor feeding, Short Stature, Microcephaly)

HPOFreeText: Phenotypes recorded postnatally. Brain MRI at 7 years showed phenotypes including small anterior commissure and blunting of rostrum.

CaseNotHPOs HP:0001250, HP:0000708, HP:0001285, HP:0002334, HP:0002119, HP:0007361, HP:0025100, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0000047, HP:0000028, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0000256, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Seizures, Behavioral problems, Spastic quadriparesis, Abnormality of cerebellar vermis, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Hypospadias, Cryptorchidism, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Macrocephaly, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Digital Anomalies, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting Tested negative for presence of de novo c.3382_3383delGA variant in ANKRD11 that twin sister had.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with sanger sequencing in patient and parents

Variant NM_012102.3:c.1411G>A(p.Val471Ile), de novo

ClinVar n/a

CAID CA571729

gnomAD 0.0001824(other), 0.00002032(total)

VariantEvidence n/a

CaseAddInfo Compound heterozygous for a frameshift and missense variant in FSIP2, encodes a sperm flagellum protein and is not currently associated with a human disease. Healthy older sister, but twin sister has KBG syndrome brought on by de novo deletion variant in ANKRD11 gene.

CasePMIDs n/a

Case# Subject 6, female, 6yo, Northern European/Hispanic

CasePresentingHPOs HP:0001263, HP:0001252, HP:0002938, HP:0000256, HP:0000325, HP:0000316, HP:0045075, HP:0011229, HP:0000368, HP:0000463, HP:0000319, HP:0012170, HP:0012168, HP:0001270, HP:0000750, HP:0000708, HP:0002311, HP:0000316, HP:0200055, HP:0011297 (Global developmental delay, Hypotonia, Lumbar lordosis, Macrocephaly, Triangular face, Sparse eyebrows, Broad eyebrows, Low-set-posteriorly rotated ears, Anteverted nares, Flat philtrum, Nail biting, Head bainging, Motor delay, Speech delay, Behavioral problems, Diifficulties in Coordination, Hypertelorism, Small hands, Digital anomalies)

HPOFreeText: Speech and motor delay noted at 2 years. Mildly flattened philtrum and remaining phenotypes presented postnatally.

CaseNotHPOs HP:0001250, HP:0001285, HP:0007018, HP:0011968, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0001159, HP:0001385, HP:0002650, HP:0001511, HP:0000098, HP:0004322, HP:0000252, HP:0011328, HP:0002007, HP:0000601, HP:0000582, HP:0000494, HP:0045025, HP:0000286, HP:0000490, HP:0004467, HP:0000414, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Seizures, Spastic quadriparesis, ADHD, Poor feeding, Coloboma, Optic Atrophy, Microphthalmia, Peter's anomaly, Iris abnormality, Blepharophimosis, Senseorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidneys, Syndactyly, Hip dysplasia, Scoliosis, Intrauterine growth retardation, Tall stature, Short stature, Microcephaly, Fontanel abnormality, Frontal bossing, Hypotelorism, Upslanted palpebral fissures, Downslanted palpebral fissures, small palpebral fissures, Epicanthus, Deep set eyes, Preauricular pits, Bulbous nose, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipple, Inverted nipples, Small hands, Clinodactyly of the 5th finger, Digital anomalies, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Cafe-au-lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmer with sanger

Variant NM_012102.3:c.3122delC(p.Pro1041Lysfs∗40)

ClinVar n/a

CAID CA658820831

gnomAD n/a

VariantEvidence n/a

CaseAddInfo unknown if de novo like the rest, no parent testing. Family history of intellectual disability and mental illness also suggests it may not be de novo. Speculated that due to deletion being in exon 17 or 21 that NMD will occur.

CasePMIDs n/a

list of some common phenoypes:

MONDO

Case# Subject 4, female, 9yo, Northern European

CasePresentingHPOs HP:0001252, HP:0002342, HP:0001250, HP:0001999, HP:0002020, HP:0001385, HP:0000076, HP:0002079, HP:0001320, HP:0006808, HP:0001943, HP:0005968, HP:0000490, HP:0000286, HP:0000356, HP:0000221, HP:0010490, HP:0011304, HP:0001156, HP:0000708, (Hypotonia, Moderate intellectual disability, Seizures, Dysmorphic facies, Gastroesophageal reflux, Hip dysplasia, Vesicoureteral reflux, Thin corpus callosum, Cerebellar vermis hypoplasia, Cerebral hypomyelination, Hypoglycemia, Temperature instability, Deep set eyes, Epicanthus, Auricle abnormality, Furrowed tongue, Abnormal palmar creases, broad thumbs, Brachydactyly, Behavioral problems)

HPOFreeText: Fleshy auricles, deep furrow in posterior third of tongue, bilateral single palmar creases, mild brachydactyly, developmental hip dysplasia, severe vesicoureteral reflux, severe behavioral issues and other phenotypes are postnatal. Brain MRI results including diminished cerebellar vermis with deep fissures at 1 year of age.

CaseNotHPOs HP:0001285, HP:0007018, HP:0011968, HP:0002119, HP:0007361, HP:0025100, HP:0030301, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002247, HP:0001734, HP:0002021, HP:0000107, HP:0001159, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0004322, HP:0000256, HP:0000252, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0000494, HP:0045025, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Spastic quadriparesis, ADHD, Poor feeding, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Abnormality of the anterior commissure, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies,Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Duodenal atresia, Annular pancreas, Pyloric stenosis, Cystic kidney, Syndactyly, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Short stature, Macrocephaly, Microcephaly, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Down-slanting palpebral fissures, Small palpebral fissures, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with Sanger in pateint and parents

Variant NM_012102.3:c.4293C>G(p.His1431Gln), de novo

ClinVar n/a

CAID CA338168808

gnomAD n/a

VariantEvidence n/a

CaseAddInfo mosaic, de novo SCN2A missense variant. SCN2A associated with 613721 and 607745

CasePMIDs n/a

Case# Subject 10, female, 14yo, non-Hispanic

CasePresentingHPOs HP:0010535, HP:0002098, HP:0031064, HP:0000729, HP:0000750, HP:0001249, (Sleep apnea, Difficulty breathing, Impaired continence, Autism spectrum disorder, Speech delay, Intellectual disability)

HPOFreeText: Phenotypes described postnatally.

CaseNotHPOs HP:0001250, HP:0001252, HP:0000708, HP:0001285, HP:0007018, HP:0011968, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0000494, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0010490, HP:0000349, HP:0004532, HP:0000957 (Seizures, Hypotonia, Behavioral problems, Spastic quadriparesis, ADHD, Poor feeding, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Down-slanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Digital Anomalies, Nail hypoplasia, Abnormal palmar creases, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting Screen for variants involved with Autism, de novo RERE variant was only result

CaseMethod1 Exome sequencing

CaseMethod2 sanger

CaseGenotypingMethod exome sequencing confirmed with sanger in patient and parents by Krumm et al.

Variant NM_012102.3:c.2278C>T(p.Gln760Ter), de novo

ClinVar n/a

CAID CA338172916

gnomAD n/a

VariantEvidence n/a

CaseAddInfo both parents tested

CasePMIDs 25961944