Family Name: Family 4

FamilyPresentingHPOs: HP:0000705

FamilyNotHPOs:

CountryOrigin: Turkey

Ethnicity: Turkish

Race: n/a

FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing

FamilyGenotypingMethod: WES, haplotype analysis

Affected: 2

Unaffected: 2

Segregations: 1

PublishedLOD: n/a

eLOD: 0.85

AddSegregationInfo: non-consanguineous family

ProbandLabel: Family 4: III:1, female, 10 yo

Variant: NM_033068.2(ACP4):c.713C>T (p.Ser238Leu)

ClinVar or CAID: 374862, https://www.ncbi.nlm.nih.gov/clinvar/variation/374862/

genomAD: 8.127e-6, http://gnomad.broadinstitute.org/variant/19-51297008-C-T

FamilyAddInfo: parents unaffectd

CasePresentingHPOs: HP:0006297, HP:0011073, HP:0006316

CasePresentingHPOTerm: hypoplasia of dental enamel, black staining of cervical teeth, large dental spacing due to thin enamel

CaseNotHPOs: HP:0010299

AddCaseInfo:

VariantEvidence:

Family Name: Family 6

FamilyPresentingHPOs: HP:0000705

FamilyNotHPOs:

CountryOrigin: Turkey

Ethnicity: Turkish

Race: n/a

FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing

FamilyGenotypingMethod: WES

Affected: 2

Unaffected: 3

Segregations: 1

PublishedLOD: n/a

eLOD: 1.0

AddSegregationInfo: non-consanguineous family

ProbandLabel: Family 6: III:1, female, 11 yo

Variant 1: NM_033068.2(ACP4):c.382G>C (p.Ala128Pro)

ClinVar or CAID: 374865, https://www.ncbi.nlm.nih.gov/clinvar/variation/374865/

genomAD: 2.449e-5, http://gnomad.broadinstitute.org/variant/19-51294991-G-C

Variant 2: NM_033068.2(ACP4):c.397G>A (p.Glu133Lys)

ClinVar: 374866, https://www.ncbi.nlm.nih.gov/clinvar/variation/374866/

genomAD: 8.196e-6, http://gnomad.broadinstitute.org/variant/19-51295006-G-A

FamilyAddInfo: parents unaffected

CasePresentingHPOs: HP:0006297, HP:0011077, HP:0000698

CasePresentingHPOTerm: hypoplastic enamel, destructed first molars, mandibular anterior teeth had incisal edges,

CaseNotHPOs: HP:0011073

AddCaseInfo: compound heterozygous mutations

VariantEvidence:

Family Name: Family 3

FamilyPresentingHPOs: HP:0000705

FamilyNotHPOs:

CountryOrigin: Turkey

Ethnicity: Turkish

Race: n/a

FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing

FamilyGenotypingMethod: WES

Affected: 2

Unaffected: 2

Segregations: 1

PublishedLOD: n/a

eLOD: 0.85

AddSegregationInfo: consanguineous marriage of first cousins

ProbandLabel: Family 3: IV:2, male

Variant: NM_033068.2(ACP4):c.226C>T (p.Arg76Cys)

ClinVar or CAID: 374864, https://www.ncbi.nlm.nih.gov/clinvar/variation/374864/

genomAD: 3.422e-5, http://gnomad.broadinstitute.org/variant/19-51294040-C-T

FamilyAddInfo: Parents unaffected

CasePresentingHPOs: HP:0000687, HP:0011073, HP:0006297

CasePresentingHPOTerm: generalized dental spacing, yellow/black discoloration of enamel, thin enamel on incisors and posterior teeth

CaseNotHPOs: HP:0000689, HP:0006479, HP:0006336

AddCaseInfo:

VariantEvidence:

Family Name: Family 5

FamilyPresentingHPOs: HP:0000705

FamilyNotHPOs:

CountryOrigin: Turkey

Ethnicity: Turkish

Race: n/a

FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing

FamilyGenotypingMethod: WES

Affected: 1

Unaffected: 4

Segregations: n/a

PublishedLOD: n/a

eLOD: n/a

AddSegregationInfo: non-consanguineous family

ProbandLabel:

Variant: NM_033068.2(ACP4):c.713C>T (p.Ser238Leu)

ClinVar or CAID: 374862, https://www.ncbi.nlm.nih.gov/clinvar/variation/374862/

genomAD: 8.127e-6, http://gnomad.broadinstitute.org/variant/19-51297008-C-T

FamilyAddInfo: parents unaffected

CasePresentingHPOs: HP:0006316, HP:0006297, HP:0011055, HP:0011079, HP:0011073

CasePresentingHPOTerm: wide interdental spacing due to thin enamel, missing second mandibular permanent molar, maxillary canine not yet erupted, black staining on maxillary anterior teeth and first permanent molars, brown staining on posterior teeth

CaseNotHPOs: HP:0010299

AddCaseInfo:

VariantEvidence:

FamilyName: Family 1

FamilyPresentingHPOs: HP:0000685

FamilyNotHPOs:

CountryOrigin: Pakistan

Ethnicity: Pakistani

Race: Asian

FamilyPreviousTesting:

FamilyMethod1: WES

FamilyMethod2:

FamilyGenotypingMethod: Whole exome sequencing identified 27 regions of homozygosity for Family 1, specifically from WES of the proband IV:3 (Supplemental Table 3).

Affected: 2

Unaffected: 1

Segregations: 1

Consanguineous: yes

PublishedLOD: n/a The minimum requirement for segregation inclusion is not met according to the ClinGen SOP version 6.

eLOD: n/a

AddSegregationInfo:

ProbandLabel: Family 1-IV:3, female

Variant: NM_033068.2(ACP4):c.746C>T (p.Pro249Leu)

Homozygous

ClinVar: 375694

gnomAD: n/a

FamilyAddInfo: WES identified 27 regions of homozygosity for Family 1 (Supplemental Table 3).

Variant deposited into the Leeds AI repository in LOVD, variant #0000000186.

FamilyPMIDs:

CasePresentingHPOs: Hypermineralization of dentine

CaseNOTHPOS: HP:0010299

CasePreviousTesting: n/a

CaseGenotypingMethod: WES identified 27 regions of homozygosity in which 2 genes, other than ACPT were flagged. These 2 genes/ variants are ZNF534:c.118A>C(p.N40H) (gnomAD AF= 0.00025 62 hets, 1 homo) and TCOF1:c.431C>T(p.T144I) (gnomAD AF= 8.12E-4, 2 hets, no homozygous; Gene Associated with Treacher collins syndrome). These variants segregated with disease along with the ACPT variation.

VariantEvidence: n/a

FamilyName: Family 2

FamilyPresentingHPOs: HP:0000685

FamilyNotHPOs:

CountryOrigin: Pakistan

Ethnicity: Pakistani

Race: Asian

FamilyPreviousTesting: n/a

FamilyMethod1: WES

FamilyMethod2:

FamilyGenotypingMethod: Whole exome sequencing identified 26 regions of homozygosity for Family 1, specifically from WES of the proband IV:3 (Supplemental Table 4).

Affected: 1

Unaffected: 2

Segregations: 0

Consanguineous: yes

PublishedLOD: n/a The minimum requirement for segregation inclusion is not met according to the ClinGen SOP version 6.

eLOD: n/a

AddSegregationInfo: Three other siblings were not tested for the variant, and appeared to not have the phenotype, including a set of twins (whether dizygotic or monozygotic was not noted).

ProbandLabel: Family 2-IV:2, female

Variant: NM_033068.2(ACP4):c.428C>T (p.Thr143Met)

Assumed Homozygous, only the mother was tested for the ACPT mutation, not the father.

ClinVar: 375700

gnomAD: MAF= 0.0001592 (Other 1/6282) AFt=5.210E-4, no homozygotes.

FamilyAddInfo: WES identified 26 regions of homozygosity for Family 1 (Supplemental Table 4).

Variant deposited into the Leeds AI repository in LOVD, variant #0000000187.

FamilyPMIDs:

CasePresentingHPOs:

CaseNOTHPOS:

CasePreviousTesting: n/a

CaseGenotypingMethod: WES identified 26 regions of homozygosity in which 2 genes, other than ACPT were flagged. These 2 genes/ variants are C18orf25:c.517G>C(p.G172C) (not in gnoMAD) and BTBD7:c.1083G>T(p.K361N) (in gnoMAD, 176 hets and 1 homozyoug AF= 0.007). These variants segregated with disease along with the ACPT variation.