Case#: Mykykyn_2002_Proband_PR1-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant in the homozygous state.

ClinVar ID: 12143

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

CaseAddInfo: The proband's family is described as consanguineous.

CasePMIDs: N/A

PMID: 12118255

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: Mykykyn_2002_Proband_D, gender not specified, age not described, family origin reported as from Turkish

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.851del (p.Tyr284fs) variant in the homozygous state.

ClinVar ID: 12146

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00001758 (2 alleles out of 113768 total alleles, with 0 homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-66290946-TA-T?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.851del (p.Tyr284fs) is a frameshift variant in exon 10 of 17 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 52% of the protein product.

CaseAddInfo: The proband's family is described as consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR2-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant in the homozygous state.

ClinVar ID: 12144

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband's family is described as consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR5-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) and NM_024649.5(BBS1):c.432+1G>A variants in the compound heterozygous state.

ClinVar ID: 12144, 12145

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.432+1G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. NM_024649.5(BBS1):c.432+1G>A is a canonical splice site variant in intron 4 that does not have experimental evidence of impact on the gene product.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Mykykyn_2002_Proband_PR3-1, gender not specified, age not described, family origin reported as from Puerto Rico

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.

CaseMethod1: linkage mapping

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) and NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variants in the compound heterozygous state.

ClinVar ID: 12144, 12143

gnomAD: The NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1 gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product. NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

PMID: 27032803

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: Bravo-Gil_2016_Proband_488, sex not specified, onset at birth, family origin reported as Spanish

CasePresentingHPOs: HP:0000618 (Blindness), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010442 (Polydactyly). HP:0001249 (Intellectual disability), HP:0001513 (Obesity)

CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of Bardet-Biedl syndrome. Reduced visual acuity was the first visual symptom. The patient is now described as having total blindness.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants

CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.118del (p.Cys40fs) variants in the compound heterozygous state.

ClinVar ID: 12143, 802688

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.118del (p.Cys40fs) variant is found in gnomAD v2.1.1 at a frequency of 0.00005782 (2 alleles / 34592 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66278553-CT-C?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.118del (p.Cys40fs) is a frameshift variant in exon 2 of 17 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 93% of the protein product.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Bravo-Gil_2016_Proband_95, sex not specified, age 7 years at onset, family origin reported as Spanish

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0000550 (Undetectable electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of simplex retinitis pigmentosa. Night blindness was the first visual symptom.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants

CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1474-2A>G variants in the compound heterozygous state.

ClinVar ID: 12143

CAID: CA381424925

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1474-2A>G variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1474-2A>G is a canonical splice site variant in intron 14 that is predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

Case#: Delvallée_2021_Proband_D.II-2, female, age not described, family origin reported as from Denmark and Sweden, ancestry reported as European

CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0001162 (Postaxial hand polydactyly), HP:0030084 (Clinodactyly), HP:0001513 (Obesity), HP:0000119 (Abnormality of the genitourinary system)

CaseHPOFreeText: The proband additionally exhibits slow ideation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.

ClinVar ID: 12143, 981241

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.

CaseAddInfo: The proband's family indicates segregation of the two variants from the two heterozygous unaffected carrier parents.

CasePMIDs: N/A

Case#: Delvallée_2021_Proband_B.II-1, male, age not described, family origin reported as from western France, ancestry reported as European

CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0000639 (Nystagmus), HP:0001162 (Postaxial hand polydactyly), HP:0001156 (Brachydactyly), HP:0001513 (Obesity), HP:0001256 (Intellectual disability, mild), HP:0001270 (Motor delay), HP:0000054 (Micropenis), HP:0000028 (Cryptorchidism)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.

ClinVar ID: 12143, 981241

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.

CaseAddInfo: The proband's family includes two similarly affected brothers sharing the same genotype.

CasePMIDs: N/A

PMID: 33169370

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

PMID: 20038682

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

ExperimentName: bbs1-1 Chlamydomonas have full-length flagella and normal IFT function but are nonphototactic.

NonHumanModel: Chlamydomonas reinhardtii

GeneAlteration: The bbs1-1 model animals have been identified as naturally occurring mutants with deletion of approximately half of the BBS1 gene as well as a separate gene unstream of BBS1.

ModelPhenotype: abnormal flagellar motility (inability to perform phototaxis), flagellar absence of BBSome components (specifically BBS4)

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: The mutants lack the ability to perform phototaxis, which is common among all BBSome mutants tested (described in text but data not shown). Flagella from the mutant show loss of BBS4 localization (Figure 4C). However, flagellar length was normal (Figure 2B) and flagellar regeneration was normal as well (described in text but data not shown).

ModelVariant: This model had a naturally occurring deletion disrupting BBS1 but did not feature knock-in of a known variant from the human patient population.

PMID: 24069149

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

ExperimentName: Morpholino-based knockdown of zbbs1 disrupts ciliary beating pattern.

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to morpholino-based knockdown of zbbs1, the zebrafish ortholog of human BBS1.

ModelPhenotype: HP:0012262 (Abnormal ciliary motility), HP:0000107 (Renal cyst)

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: Morpholino-based knockdown of the zbbs1 gene causes hydrocephalus (Figure 3B), formation of pronephritic cysts (Figure 3G), embyronic body axis abnormalities (Figure 4B), heart looping defects (Figure 5B), longer cilia (Figure 7F), and normal ciliary ultrastructure (Figure 7I), and aberrant ciliary motility in the pronephritic tubule and nasal pit (Supplementary Movies).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied the effects of silencing the gene product.

ExperimentName: Knock-in of the p.M390R variant into the mouse Bbs1 gene.

NonHumanModel: Mus musculus

GeneAlteration: The model animals have been subjected to homologous recombination-based knock-in of the p.M390R variant into exon 12 of the endogenous mouse Bbs1 gene. The variant has been studied in the homozygous state.

ModelPhenotype: HP:0032558 (Absent sperm flagella), HP:0010633 (Partial anosmia), HP:0012433 (Abnormal social behavior), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001513 (Obesity), HP:0002119 (Ventriculomegaly),

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: Sperm flagella were absent (Figures 2A, 2B). Loss of the outer nuclear layer and degeneration of the photoreceptor inner and outer segments were observed in older mice (Figures 2C, 2D). Photoreceptor morphology in the outer segment was also disrupted in TEM images (Figure 2E). Scotopic responses showed a- and b-wave attenuation (Figure 2G), while photopic responses were not significantly different (Figure 2H). Homozygous mice showed obesity relative to wild-type and heterozygous mice (Figure 3). Brain sections showed neuroanatomical defects, especially ventriculomegaly (Figure 4). Brain cilia were morphologically abnormal (Figure 5). Renal cysts and polydactyly were investigated but not observed.

ModelVariant: This model introduced a disease-associated variant known from affected human patients (NM_024649.5(BBS1):c.1169T>G (p.Met390Arg), ClinVar ID: 12143).

PMID: 18032602

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: Harville_2010_Patient_A2885–II2, sex and age not reported, family origin reportedly from Saudi Arabia

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy), HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000077 (Abnormality of the kidney), HP:0001249 (Intellectual disability), HP:0004322 (Short stature), HP:0001263 (Global developmental delay), HP:0000823 (Delayed puberty)

CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease.

CaseMethod1: homozygosity mapping

CaseMethod2: Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

CaseGenotypingMethod: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease. This was followed by Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

Variant: The proband harbors the NM_024649.5(BBS1):c.124+1G>A variant in the homozygous state.

ClinVar ID: 557428

gnomAD: The NM_024649.5(BBS1):c.124+1G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.124+1G>A is a canonical splice site variant in intron 2 that is predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family is reportedly consanguineous and includes a similarly affected sibling sharing the same homozygous genotype.

CasePMIDs: N/A

PMID: 19797195

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: Harville_2010_Patient_A2014-II1, sex assumed to be male based on phenotypes, age not reported, family origin reportedly from Turkey

CasePresentingHPOs: HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000135 (Hypogonadism), HP:0000077 (Abnormality of the kidney)

CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome. Secondary signs are noted as present, but specifics are not reported.

CaseNotHPOs: HP:0000510 (Rod-cone dystrophy)

CaseNotHPOFreeText: The proband reportedly does not have retinitis pigmentosa. Age has not been reported in the study.

CasePreviousTesting: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease.

CaseMethod1: homozygosity mapping

CaseMethod2: Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

CaseGenotypingMethod: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease. This was followed by Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.

Variant: The proband harbors the NM_024649.5(BBS1):c.48-1G>A variant in the homozygous state.

ClinVar ID: 1299580

gnomAD: The NM_024649.5(BBS1):c.48-1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.000008790 in the European (non-Finnish) population, with 1 allele / 113768 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66278483-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.48-1G>A is a canonical splice site variant predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family is reportedly consanguineous.

CasePMIDs: N/A

PMID: 23847139

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: Wang_2013_Patient_704, female, age 9 years at onset, family origin not reported

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000822 (Hypertension), HP:0000858 (Irregular menstruation), HP:0025502 (Overweight)

CaseHPOFreeText: The proband has a diagnosis of juvenile retinitis pigmentosa. Visual acuity was limited to hand movements and later to light perception. Patient is described as slightly overweight.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to capture-based next-generation sequencing panel that included 163 known retinal disease genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: SNP array and Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was genotyped by capture-based next-generation sequencing panel that included 163 known retinal disease genes. SNP array and Sanger sequencing of BBS1 were subsequently used to confirm the presence of the variant.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant in the homozygous state.

ClinVar ID: 12143

gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant.

CaseAddInfo: The variant reportedly segregates with disease within the proband's family, but details are not available.

CasePMIDs: N/A

PMID: 22072986

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0034464 (BBSome)

FunctionalEvidence: Affinity-purified human BBS4 expressed from a transgene in mouse testes resulted in co-purification of all BBSome subunits, including Bbs1, as identified by mass spectrometry (Figure 1A).

FunctionalHPO: HP:0000026 (Male hypogonadism), HP:0000510 (Rod-cone dystrophy), HP:0001513 (Obesity)

PMID: 33910932

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

PMID: 12524598

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

PMID: 23143442

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.