ExperimentName: Mutt mice have a FBXO11 S244L mutation

NonHumanModel: mouse (mus musculus)

GeneAlteration: ENU (ethylnitrosourea) was used to induce random mutatgeneiss in the mouse (PMID: 10932191). Animals were screened based on the development of otitis media. Sequencing of the mouse genome uncovered a single point mutation in the FBXO11 gene resulting in a Ser244Leu protein change. This mutation occurs in the region between the F-box and CASH domain. The Ser at amino acid position 244 is conserved across several species.

ModelPhenotype: HP:0000708

Also cleft palate and craniofacial abnormalities

HumanPhenotype: HP:0000708

ModelEvidence: The Mutt mutant mice have a point mutation in FBXO11, S244L. Heterozygous Mutt mice displayed reduced startle reflex at postnatal day 48. They also showed mild cranialfacila abnormalities including a shortened face. The Mutt homozygtote mice demonstrated perinatal lethality within the first day after birth in 17% of mice, but was much less severe than the Jeff mutant mice. the Jeff mice. Furthermore, that homozygotes mice had mild cleft palate and variable facial clefting, and the surviving homozygotes went on to develop craniofacial abnormalities including short face as well as reduced hearing.

ModelVariant: NM_001190274.1:c.983C>T (p. Ser328Leu) equivalent to ENST00000402508.5:c.731C>T (p. Ser244Leu)

CA ID: CA346766144

ExperimentName: Mutt mice have a FBXO11 S244L mutation

NonHumanModel: mouse (mus musculus)

GeneAlteration: ENU (ethylnitrosourea) was used to induce random mutatgeneiss in the mouse (PMID: 10932191). Animals were screened based on the development of otitis media. Sequencing of the mouse genome uncovered a single point mutation in the FBXO11 gene resulting in a Ser244Leu protein change. This mutation occurs in the region between the F-box and CASH domain. The Ser at amino acid position 244 is conserved across several species.

ModelPhenotype: HP:0000708

Also cleft palate and craniofacial abnormalities

HumanPhenotype: HP:0000708

ModelEvidence: The Mutt mutant mice have a point mutation in FBXO11, S244L. Heterozygous Mutt mice displayed reduced startle reflex at postnatal day 48. They also showed mild cranialfacila abnormalities including a shortened face. The Mutt homozygtote mice demonstrated perinatal lethality within the first day after birth in 17% of mice, but was much less severe than the Jeff mutant mice. the Jeff mice. Furthermore, that homozygotes mice had mild cleft palate and variable facial clefting, and the surviving homozygotes went on to develop craniofacial abnormalities including short face as well as reduced hearing.

ModelVariant: NM_001190274.1:c.983C>T (p. Ser328Leu) equivalent to ENST00000402508.5:c.731C>T (p. Ser244Leu)

CA ID: CA346766144

Case: Individual 11, male, AOR= 14 years

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0001256, HP:0000752, HP:0001575, HP:0000276, HP:0000286, HP:0000278, HP:0000347, HP:0001182, HP:0001763, HP:0001852, HP:0011330, HP:0001382, HP:0002719, HP:0000540, HP:0000486, HP:0002967, HP:0001065, HP:0001724, HP:0010499, HP:0000243

CasePresentingHPOText: Began walking at 24 months old.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0012443,

CasePreviousTesting: Array-CGH (244K Agilent) normal, Fragile X syndrome (FMR1 Repeat analysis) normal, Loeys-Dietz syndrome (TGFBR1 and TGFBR2) normal and Marfan syndrome (FBN1) normal

CaseGenotypingMethod: WES (Agilent CRE and HiSeq 4000), searching for variants in FBXO11 after identification of variant in I13, Sanger confirmation to show de novo status and absence in parents. Sample identity confirmed.

Variant: hg19:chr2: g.4806002 0C>G, c.1042- 1G>C, p.(?) OR NM_001190274.1:c.1042- 1G>C(p.=)

CA ID: CA346765998

de novo splice site mutation.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The c.1042-1G>C mutation is most likely a splice site mutation. The mutation arises in exon 9 (Intron 8), and likely would disrupt exon 9 transcription. Exon 9 does not transcirbe any of the funcitonal domains, but exon 10 comprises the NosD domain, which is 5' to the first CASH domain. No functional assays or variant evidence was provided, so I have downgraded the score.

Case: Individual 2, female, AOR= 8yo

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0002342, HP:0007359, HP:0002500, HP:0001290, HP:0002360, HP:0000729, HP:0000739, HP:0025269, HP:0000490, HP:0001840, HP:0000486

CasePResentingHPOText: Began walking at 22 months, first words at 2yo,. Seizure onset at 7 yo and are focal, and occur nightly. Reduced white matter bulk on MRI. Referred to as having intoeing or pigeon-toed. Low APGAR scores, brief resuscitation required

CaseNOTHPOs: HP:0002376, HP:0000202, HP:0000924, HP:0002719,

CasePreviousTesting: ArrayCGH, Fragile X (FMR1), Angelman Syndrome (methylation & UBE3A), Rett syndrome (MECP2), Pitt-Hopkins Syndrome (TCF4), and extensive metabolic screening were all normal

CaseGenotypingMethod: Trio-WES performed through the DDD consortium, 2017 PMID:PMID: 28135719.

Variant: hg19:chr2: g.48066586T>A, c.414A>T, p.(Arg138Ser) or NM_001190274.1:c.414A>T

CA ID: CA346813374

de novo Trio-WES performed by DDD so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo: Case was part of the DDD study 2017 PMID: 28135719,

VariantEvidence: Arg138 is located N-terminal to the F-box region of FBXO11, and is conserved across species. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the R138S mutation on FBXO11 function.

Case: Individual 11, male, AOR= 14 years

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0001256, HP:0000752, HP:0001575, HP:0000276, HP:0000286, HP:0000278, HP:0000347, HP:0001182, HP:0001763, HP:0001852, HP:0011330, HP:0001382, HP:0002719, HP:0000540, HP:0000486, HP:0002967, HP:0001065, HP:0001724, HP:0010499, HP:0000243

CasePresentingHPOText: Began walking at 24 months old.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0012443,

CasePreviousTesting: Array-CGH (244K Agilent) normal, Fragile X syndrome (FMR1 Repeat analysis) normal, Loeys-Dietz syndrome (TGFBR1 and TGFBR2) normal and Marfan syndrome (FBN1) normal

CaseGenotypingMethod: WES (Agilent CRE and HiSeq 4000), searching for variants in FBXO11 after identification of variant in I13, Sanger confirmation to show de novo status and absence in parents. Sample identity confirmed.

Variant: hg19:chr2: g.4806002 0C>G, c.1042- 1G>C, p.(?) OR NM_001190274.1:c.1042- 1G>C(p.=)

CA ID: CA346765998

de novo splice site mutation.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The c.1042-1G>C mutation is most likely a splice site mutation. The mutation arises in exon 9 (Intron 8), and likely would disrupt exon 9 transcription. Exon 9 does not transcirbe any of the funcitonal domains, but exon 10 comprises the NosD domain, which is 5' to the first CASH domain. No functional assays or variant evidence was provided, so I have downgraded the score.

Case: Individual 2, female, AOR= 8yo

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0002342, HP:0007359, HP:0002500, HP:0001290, HP:0002360, HP:0000729, HP:0000739, HP:0025269, HP:0000490, HP:0001840, HP:0000486

CasePResentingHPOText: Began walking at 22 months, first words at 2yo,. Seizure onset at 7 yo and are focal, and occur nightly. Reduced white matter bulk on MRI. Referred to as having intoeing or pigeon-toed. Low APGAR scores, brief resuscitation required

CaseNOTHPOs: HP:0002376, HP:0000202, HP:0000924, HP:0002719,

CasePreviousTesting: ArrayCGH, Fragile X (FMR1), Angelman Syndrome (methylation & UBE3A), Rett syndrome (MECP2), Pitt-Hopkins Syndrome (TCF4), and extensive metabolic screening were all normal

CaseGenotypingMethod: Trio-WES performed through the DDD consortium, 2017 PMID:PMID: 28135719.

Variant: hg19:chr2: g.48066586T>A, c.414A>T, p.(Arg138Ser) or NM_001190274.1:c.414A>T

CA ID: CA346813374

de novo Trio-WES performed by DDD so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo: Case was part of the DDD study 2017 PMID: 28135719,

VariantEvidence: Arg138 is located N-terminal to the F-box region of FBXO11, and is conserved across species. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the R138S mutation on FBXO11 function.