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

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

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: 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.

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.

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)

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