Activity

Filter

Cancel
Date Panel Item Activity
348 actions
Amelogenesis imperfecta v4.30 ALPL Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported in literature with both mono- and bi- allelic ALPL variants, with hypophosphatasia. Tooth loss and other dental signs are very common symptoms, particularly in paediatric-onset cases. Odontohypophosphatasia cases present with an isolated dental phenotype. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next update.; to: Comment on list classification: There are numerous individuals reported in literature with both mono- and bi- allelic ALPL variants, diagnosed with hypophosphatasia. Tooth loss and other dental signs are very common symptoms, particularly in paediatric-onset cases. Odontohypophosphatasia cases present with an isolated dental phenotype. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next update.
Amelogenesis imperfecta v4.30 ALPL Ida Ertmanska Classified gene: ALPL as Amber List (moderate evidence)
Amelogenesis imperfecta v4.30 ALPL Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported in literature with both mono- and bi- allelic ALPL variants, with hypophosphatasia. Tooth loss and other dental signs are very common symptoms, particularly in paediatric-onset cases. Odontohypophosphatasia cases present with an isolated dental phenotype. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next update.
Amelogenesis imperfecta v4.30 ALPL Ida Ertmanska Gene: alpl has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.29 ALPL Ida Ertmanska Phenotypes for gene: ALPL were changed from to Odontohypophosphatasia, OMIM:146300; hypophosphatasia, MONDO:0018570
Amelogenesis imperfecta v4.28 ALPL Ida Ertmanska Publications for gene: ALPL were set to
Amelogenesis imperfecta v4.27 ALPL Ida Ertmanska Mode of inheritance for gene: ALPL was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Amelogenesis imperfecta v4.26 ALPL Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ALPL.
Amelogenesis imperfecta v4.26 ALPL Ida Ertmanska reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500388, 34164522, 36101824, 39983296; Phenotypes: Odontohypophosphatasia, OMIM:146300, hypophosphatasia, MONDO:0018570; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Amelogenesis imperfecta v4.25 ALPL Claire Smith gene: ALPL was added
gene: ALPL was added to Amelogenesis imperfecta. Sources: Literature,Expert Review
Mode of inheritance for gene: ALPL was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Penetrance for gene: ALPL were set to Complete
Review for gene: ALPL was set to GREEN
Added comment: According to the review of ALPL literature, PMID: 39872235
"78.8% of adults with pediatric-onset HPP have dental involvement vs 42.6% of those with adult-onset HPP."
"clinical observations can include enamel hypoplasia and discoloration (possibly contributing to increased caries prevalence), delayed tooth eruption, tooth mobility, and malocclusion (misalignment of upper and lower teeth due to incorrect positions along the dental arches)"

(Note that enamel hypoplasia, although it can mean just specific teeth being affected, is also a term often used to reflect amelogenesis imperfecta in the presence of diseases affecting other organ systems, this is because the original definition of amelogenesis imperfecta excluded it being part of syndromic diseases, this is now changing)

According to Chavez et al.'s ALPL review PMID: 32758526
"Ameloblasts, odontoblasts, cementoblasts, osteoblasts, and periodontal ligament (PDL) cells express TNAP (encoded by ALPL) ( (Bowden and Foster, 2019, Zweifler et al., 2015), indicating the enzyme may function in all aspects of dental and periodontal mineralization."

ALPL is also included on the panel used by Fulgent genetics to screen patients with amelogenesis imperfecta
https://fulgentgenetics.com/Amelogenesis-Imperfecta
Sources: Literature, Expert Review
Amelogenesis imperfecta v4.25 SMARCD2 Ida Ertmanska commented on gene: SMARCD2: Comment on list classification: While there are several cases reported with biallelic SMARCD2 variants and a 'dental' phenotype, the symptoms are very mild and they do not fit into the scope of this panel. Hence, this gene should remain Amber for Amelogenesis imperfecta until more evidence emerges.
Amelogenesis imperfecta v4.25 LTBP3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype correct as of 22nd Dec 2025
Amelogenesis imperfecta v4.25 LTBP3 Eleanor Williams Phenotypes for gene: LTBP3 were changed from Dental anomalies and short stature, OMIM:601216; Amelogenesis Imperfecta; syndromic AI with brachyolmia to Dental anomalies and short stature, OMIM:601216
Amelogenesis imperfecta v4.24 LTBP3 Ida Ertmanska commented on gene: LTBP3
Amelogenesis imperfecta v4.24 LTBP3 Claire Smith reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29625025; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.24 CLDN16 Achchuthan Shanmugasundram Publications for gene: CLDN16 were set to 26426912
Amelogenesis imperfecta v4.23 CLDN16 Achchuthan Shanmugasundram Phenotypes for gene: CLDN16 were changed from Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis (FHHNC) to familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.22 SMARCD2 Ida Ertmanska Phenotypes for gene: SMARCD2 were changed from Specific granule deficiency 2, 617475 to Specific granule deficiency 2, OMIM:617475
Amelogenesis imperfecta v4.21 SMARCD2 Ida Ertmanska Publications for gene: SMARCD2 were set to 28369036
Amelogenesis imperfecta v4.20 SMARCD2 Ida Ertmanska Classified gene: SMARCD2 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.20 SMARCD2 Ida Ertmanska Gene: smarcd2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.19 SMARCD2 Ida Ertmanska reviewed gene: SMARCD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28369036, 33025377, 33279574, 36135322; Phenotypes: Specific granule deficiency 2, OMIM:617475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.19 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted. WES identified a homozygous splice acceptor site variant in intron 8, c.724-2A>G in TUFT1.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.19 TUFT1 Ida Ertmanska Phenotypes for gene: TUFT1 were changed from amelogenesis imperfecta to Woolly hair-skin fragility syndrome, OMIM:620415
Amelogenesis imperfecta v4.18 TUFT1 Ida Ertmanska Publications for gene: TUFT1 were set to 7919663
Amelogenesis imperfecta v4.17 TUFT1 Ida Ertmanska Mode of inheritance for gene: TUFT1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska edited their review of gene: TUFT1: Added comment: Comment on list classification: As reviewed by Claire Smith, variants in TUFT1 are not associates with dental abnormalities. Instead, 11 individuals from 4 families with biallelic variants in TUFT1 presented with woolly hair and skin fragility. Based on the available evidence, TUFT1 should remain Red for Amelogenesis imperfecta.; Changed phenotypes to: Woolly hair-skin fragility syndrome, OMIM:620415
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. A Tuft1-knockout mouse model mimicked the patients' phenotypes. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska reviewed gene: TUFT1: Rating: ; Mode of pathogenicity: None; Publications: 25531160, 36689522, 37716648; Phenotypes: ; Mode of inheritance: None
Amelogenesis imperfecta v4.16 TP63 Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.; to: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). The association is supported by a knockout mouse model, showing absence of hair follicles, teeth and mammary glands (PMID: 10227293). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.
Amelogenesis imperfecta v4.16 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, MONDO:0011428
Amelogenesis imperfecta v4.15 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Split hand-split foot-ectodermal dysplasia and amelogenesis imperfecta to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292
Amelogenesis imperfecta v4.14 TP63 Ida Ertmanska Publications for gene: TP63 were set to
Amelogenesis imperfecta v4.13 TP63 Ida Ertmanska Classified gene: TP63 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.13 TP63 Ida Ertmanska Gene: tp63 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TP63.
Tag Q4_25_expert_review tag was added to gene: TP63.
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska edited their review of gene: TP63: Added comment: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.; Changed rating: GREEN
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska changed review comment from: PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).; to: PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Seq method: WES in probands and Sanger in family members.
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska reviewed gene: TP63: Rating: AMBER; Mode of pathogenicity: None; Publications: 10227293, 22065540, 31050217, 33126320; Phenotypes: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska changed review comment from: Comment on list classification: there are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NECTIN4.
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska Publications for gene: NECTIN4 were set to PMID: 34067522; 37183149
Amelogenesis imperfecta v4.11 NECTIN4 Ida Ertmanska edited their review of gene: NECTIN4: Changed publications to: 20691405, 21346770, 34067522, 37183149, 37829154
Amelogenesis imperfecta v4.11 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from syndactyly of the toes and fingers; hair abnormalities; variable dental genesis; enamel hypoplasia (amelogenesis imperfecta?); variable nail dystrophy; variable palmoplantar keratoderma, hyperkeratosis, reduced sweating to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.10 NECTIN4 Ida Ertmanska Classified gene: NECTIN4 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.10 NECTIN4 Ida Ertmanska Gene: nectin4 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska commented on gene: NECTIN4: Comment on list classification: there are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska changed review comment from: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.
;
PMID: 40586252 Abu Assab et al. 2025; to: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.

NECTIN4, previously known as PVRL4, is linked to Ectodermal dysplasia-syndactyly syndrome 1, 613573 (OMIM, accessed 7th Nov 2025).
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska reviewed gene: NECTIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34067522, 37183149; Phenotypes: Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573, ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: CLDN16.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska changed review comment from: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The dental defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska changed review comment from: Comment on list classification: There are at 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska commented on gene: CLDN16: Comment on list classification: There are at 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912, 32710267; Phenotypes: familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only 1 APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: AIRE.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.8 AIRE Ida Ertmanska Publications for gene: AIRE were set to PMID: 37993717; 19393987; 27253668
Amelogenesis imperfecta v4.7 AIRE Ida Ertmanska Mode of inheritance for gene: AIRE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.6 AIRE Ida Ertmanska Classified gene: AIRE as Amber List (moderate evidence)
Amelogenesis imperfecta v4.6 AIRE Ida Ertmanska Gene: aire has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska commented on gene: AIRE: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only 1 APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19393987, 27253668, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.5 TP63 Claire Smith reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:not listed; Phenotypes: ectodermal dysplasia, split hand/foot malformation, orofacial defect, dry skin, wiry hair, fewer teeth, malformed teeth, amelogenesis imperfecta, dystrophic nails, reduced sweat glands, mammary gland and nipple hypoplasia, lacrimal duct defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v4.5 SMARCD2 Claire Smith reviewed gene: SMARCD2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33279574, 28369036, 33025377, 36135322; Phenotypes: many including Amelogenesis imperfecta; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.5 NECTIN4 Claire Smith gene: NECTIN4 was added
gene: NECTIN4 was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: NECTIN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NECTIN4 were set to PMID: 34067522; 37183149
Phenotypes for gene: NECTIN4 were set to syndactyly of the toes and fingers; hair abnormalities; variable dental genesis; enamel hypoplasia (amelogenesis imperfecta?); variable nail dystrophy; variable palmoplantar keratoderma, hyperkeratosis, reduced sweating
Penetrance for gene: NECTIN4 were set to Complete
Review for gene: NECTIN4 was set to GREEN
Added comment: Evidence from literature is that loss of function variants in NECTIN4 lead to a syndromic phenotype which includes "enamel hypoplasia" a term often used when amelogenesis imperfecta occurs with other symptoms.

PMID:34067522 describes ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4. Nine other EDSS1 cases have been described prior to this report. 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in NECTIN4. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1.

PMID 37183149 reported a large Pakistani consanguineous family, the affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. NECTIN4 novel nonsense variant [c.163C>T; p.(Arg55*)]. Most likely Nectin-4 function will be lost.
Sources: Literature
Amelogenesis imperfecta v4.5 AIRE Claire Smith changed review comment from: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature; to: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature

Edit: I didn't add Amelogenesis imperfecta to the phenotype list. Can you please add this! I can't seem to add it in retrospect!
Amelogenesis imperfecta v4.5 AIRE Claire Smith gene: AIRE was added
gene: AIRE was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AIRE were set to PMID: 37993717; 19393987; 27253668
Phenotypes for gene: AIRE were set to Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis
Penetrance for gene: AIRE were set to unknown
Review for gene: AIRE was set to GREEN
Added comment: It is well reported that 70-90% of patients with APS-1 (# 240300) have enamel formation defects of various severity. These patients have mutations in the AIRE gene (see PMID 19393987;27253668).

Paper in 2023 (PMID 37993717) reported that there is autoreactivity against enamel antigens in Aire-/- mouse models and that this is also seen in (against ameloblast-specific proteins) in patients with APS-1. The authors looked at 17 patients total and saw autoantibodies in all to enamel specific proteins, see figure 1F.

Immunofluorescence microscopy analysis demonstrated largely overlapping signals from APS-1 serum with that from AMELX- and LAMB3-specific antibodies. Moreover, ELISA analyses revealed that both paediatric and adult patients with APS-1 have IgA autoantibodies against several ameloblast antigens, including LAMB3, FAM20A, ENAM and AMELX, or IgG1 autoantibodies against ACPT. Overall, all patients tested with APS-1 developed autoantibodies against at least one of the five major ameloblast antigens, with distinct reactivity clusters. Furthermore, patients with severe enamel defects had significantly higher levels of autoantibody reactivity against all of the tested enamel antigens compared with those with mild enamel defects or age-matched healthy control individuals. Moreover, canines, which have the longest mineralization period (around 6.5 years), had the most pronounced enamel defects, in comparison to incisors or first molars, of which the mineralization period is significantly shorter (around 4.5 and 3  years, respectively), suggesting that the longer the mineralization period, the higher the chance for enamel-specific autoantibodies to interfere and cause damage in enamel formation.

This is a really interesting mechanism of disease, whereby mutations in AIRE can cause the development of self antigens against the proteins that make enamel, which leads to amelogenesis imperfecta. Note that the paper does not specify whether patients were mono or biallelic carriers of the AIRE variants, note that OMIM records that both mono and balletic variants can cause APS-1.

Note that the authors also looked at patients with coeliac disease and found similar autoantibodies against enamel proteins.
Sources: Literature
Amelogenesis imperfecta v4.5 TUFT1 Claire Smith reviewed gene: TUFT1: Rating: RED; Mode of pathogenicity: None; Publications: 36689522; Phenotypes: woolly hair, skin fragility, keratosis pilaris; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.5 CLDN16 Claire Smith reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 32710267; Phenotypes: amelogenesis imperfecta, hyperparathyroidism, short stature, nephrocalcinosis, polyuria, polydipsia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.5 LAMC2 Eleanor Williams Classified gene: LAMC2 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.5 LAMC2 Eleanor Williams Added comment: Comment on list classification: Keeping the rating as amber. 1 reported case (PMID: 37228816) but with no phenotype for the mother who also carries the variant in LAMC2. Supportive mouse model in (PMID:26956061).
Amelogenesis imperfecta v4.5 LAMC2 Eleanor Williams Gene: lamc2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.4 LAMC2 Eleanor Williams Phenotypes for gene: LAMC2 were changed from Amelogenesis Imperfecta; Epidermolysis bullosa, junctional, Herlitz type, 226700; Epidermolysis bullosa, junctional, non-Herlitz type, 226650 to amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.3 LAMC2 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance to monoallelic since in the only reported case the proband was heterozygous for a variant in LAMC2.
Amelogenesis imperfecta v4.3 LAMC2 Eleanor Williams Mode of inheritance for gene: LAMC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.2 LAMC2 Eleanor Williams Publications for gene: LAMC2 were set to 26956061
Amelogenesis imperfecta v4.1 LAMC2 Claire Smith edited their review of gene: LAMC2: Added comment: PMID: 37228816 Bloch-Zupan et al. 2023 report one family with LAMC2 mutations as part of a larger panel of sequenced individuals. They report a single child as being affected with a hypoplastic/hypomature AI phenotype. The primary dentition is described as showing thin white opaque enamel.

They identified a heterozygous LAMC2 variant NM_005562.3: c.493C>T; p.(Arg165Cys) with an allele frequency of 0.2% in GnomAD, predicted deleterious by SIFT (v4.0.3) and PolyPhen-2 and located in the Laminin EGF domain. The authors highlight that the enamel formation defects in mice (Wazen et al., 2016) and the patient’s phenotype are similar to the one another. The allele is inherited from her mother but the mother's phenotype was not available.

Notably the patient was sequenced using whole exome sequencing using the following parameters: Non-pathogenic variants were filtered out via: 1) variants represented with an allele frequency of more than 1% in public variation databases including the 1,000 Genomes, the GnomAD database or their internal exome database, variants in 5′ or 3′ UTR, variants with intronic locations and no prediction of local splice effect, and synonymous variants without pathogenic prediction of local splice effect.

Annotations of structural variations (SV) were performed by AnnotSV (Geoffroy et al., 2018). No other findings are presented for the individual.

In conclusion, I do not believe this is strong enough evidence to conclude that this LAMC2 mutation is the cause of disease in this family due to the lack of phenotype information for the mother or any modelling of the effects of the variant, but it is suggestive and additional publications with further families might provide more solid evidence to elevate this gene to green. I would currently consider this gene to be rated amber.; Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2025-04-30
Amelogenesis imperfecta v4.0 Arina Puzriakova promoted panel to version 4.0
Amelogenesis imperfecta v3.11 PLXNB2 Arina Puzriakova Tag Q2_24_promote_green was removed from gene: PLXNB2.
Amelogenesis imperfecta v3.11 AMBN Arina Puzriakova Tag Q2_24_MOI was removed from gene: AMBN.
Amelogenesis imperfecta v3.11 PLXNB2 Arina Puzriakova reviewed gene: PLXNB2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.11 AMBN Arina Puzriakova reviewed gene: AMBN: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.10 PLXNB2 Arina Puzriakova Source Expert Review Green was added to PLXNB2.
Source NHS GMS was added to PLXNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Amelogenesis imperfecta v3.10 AMBN Arina Puzriakova Source NHS GMS was added to AMBN.
Mode of inheritance for gene AMBN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.9 PLXNB2 Arina Puzriakova Tag gene-checked tag was added to gene: PLXNB2.
Amelogenesis imperfecta v3.9 AMBN Achchuthan Shanmugasundram Tag Q2_24_MOI tag was added to gene: AMBN.
Amelogenesis imperfecta v3.9 AMBN Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic AMBN variants with amelogenesis imperfecta. However, only the autosomal recessive phenotype has been reported in OMIM.

The MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Amelogenesis imperfecta v3.9 AMBN Achchuthan Shanmugasundram Mode of inheritance for gene: AMBN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.8 AMBN Achchuthan Shanmugasundram Phenotypes for gene: AMBN were changed from Amelogenesis imperfecta, type IF, 616270 to Amelogenesis imperfecta, type IF, OMIM:616270
Amelogenesis imperfecta v3.7 AMBN Achchuthan Shanmugasundram Publications for gene: AMBN were set to 24858907; 26502894
Amelogenesis imperfecta v3.6 AMBN Achchuthan Shanmugasundram reviewed gene: AMBN: Rating: GREEN; Mode of pathogenicity: None; Publications: 30174330, 31402633, 38058155; Phenotypes: Amelogenesis imperfecta, type IF, OMIM:616270; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.6 PLXNB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reported in PMID:38458752 and reviewed by Claire Smith, there are seven patients from five different families (from a total of eight patients from six families) reported with amelogenesis imperfect. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reported in PMID:38458752 and reviewed by Claire Smith, there are seven patients from five different families (from a total of eight patients from six families) reported with amelogenesis imperfecta. Hence, this gene can be promoted to green rating in the next GMS update.
Amelogenesis imperfecta v3.6 PLXNB2 Achchuthan Shanmugasundram Classified gene: PLXNB2 as Amber List (moderate evidence)
Amelogenesis imperfecta v3.6 PLXNB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:38458752 and reviewed by Claire Smith, there are seven patients from five different families (from a total of eight patients from six families) reported with amelogenesis imperfect. Hence, this gene can be promoted to green rating in the next GMS update.
Amelogenesis imperfecta v3.6 PLXNB2 Achchuthan Shanmugasundram Gene: plxnb2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v3.5 PLXNB2 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: PLXNB2.
Amelogenesis imperfecta v3.5 PLXNB2 Achchuthan Shanmugasundram Phenotypes for gene: PLXNB2 were changed from Amelogenesis imperfecta; sensorineural hearing loss to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Amelogenesis imperfecta v3.4 PLXNB2 Achchuthan Shanmugasundram Publications for gene: PLXNB2 were set to PMID: 38458752
Amelogenesis imperfecta v3.3 PLXNB2 Achchuthan Shanmugasundram reviewed gene: PLXNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38458752; Phenotypes: amelogenesis imperfecta, MONDO:0019507, sensorineural hearing loss disorder, MONDO:0020678, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.3 AMBN Claire Smith edited their review of gene: AMBN: Added comment: PMID: 38058155 identifies AMBN variants that appear to cause disease in an autosomal dominant fashion.
One family has a dominant family history spanning 4 generations, and the likely causative variant in this family was also identified as monoallelic/heterozygous in 2 other apparently unrelated individuals with isolated AI.; Changed publications to: PMID: 24858907, 26502894, 38058155; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v3.3 PLXNB2 Claire Smith changed review comment from: PMID: 38458752 Smith et al. (in press) report 8 patients in 6 families with rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and sensorineural hearing loss as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases.
Sources: Literature, Expert Review; to: PMID: 38458752 Smith et al. (in press) report 8 patients in 6 families with rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and sensorineural hearing loss as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases.
Sources: Literature, Expert Review

Personal communication with Roland Friedel and Christian Junquiera-Alves regarding their findings in their Plxnb2-/- mouse model after publication of human patients with PLXNB2 variants: "We had made also initial observations in the PB2 KO mouse on cochlear defects and tooth malformations that looked interesting, but we did not follow up as I focused on cerebellar development. Now these findings look in retrospect much more exciting considering your data."
Amelogenesis imperfecta v3.3 PLXNB2 Claire Smith gene: PLXNB2 was added
gene: PLXNB2 was added to Amelogenesis imperfecta. Sources: Literature,Expert Review
Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNB2 were set to PMID: 38458752
Phenotypes for gene: PLXNB2 were set to Amelogenesis imperfecta; sensorineural hearing loss
Penetrance for gene: PLXNB2 were set to unknown
Review for gene: PLXNB2 was set to GREEN
Added comment: PMID: 38458752 Smith et al. (in press) report 8 patients in 6 families with rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and sensorineural hearing loss as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases.
Sources: Literature, Expert Review
Amelogenesis imperfecta v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2023-03-22
Amelogenesis imperfecta v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Amelogenesis imperfecta v2.22 SP6 Achchuthan Shanmugasundram Tag Q3_21_rating was removed from gene: SP6.
Amelogenesis imperfecta v2.22 PEX6 Achchuthan Shanmugasundram Tag Q1_22_MOI was removed from gene: PEX6.
Amelogenesis imperfecta v2.22 PEX26 Achchuthan Shanmugasundram Tag Q3_21_rating was removed from gene: PEX26.
Amelogenesis imperfecta v2.22 SP6 Achchuthan Shanmugasundram reviewed gene: SP6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Amelogenesis imperfecta v2.22 PEX6 Achchuthan Shanmugasundram commented on gene: PEX6
Amelogenesis imperfecta v2.22 PEX26 Achchuthan Shanmugasundram reviewed gene: PEX26: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Amelogenesis imperfecta v2.21 SP6 Achchuthan Shanmugasundram Source Expert Review Green was added to SP6.
Source NHS GMS was added to SP6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Amelogenesis imperfecta v2.21 PEX6 Achchuthan Shanmugasundram Source NHS GMS was added to PEX6.
Mode of inheritance for gene PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.21 PEX26 Achchuthan Shanmugasundram Source Expert Review Green was added to PEX26.
Source NHS GMS was added to PEX26.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Amelogenesis imperfecta v2.20 COL17A1 Arina Puzriakova Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional, non-Herlitz type, 226650 (includes enamel pitting); Amelogenesis Imperfecta; non-Herlitz junctional epidermolysis bullosa (nH-JEB) and amelogenesis imperfecta; hypoplastic amelogenesis imperfecta to Epidermolysis bullosa, junctional 4, intermediate, OMIM:619787 (includes enamel pitting); Hypoplastic amelogenesis imperfecta
Amelogenesis imperfecta v2.19 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed publications to: 29220678
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal in order to detect the dominant Peroxisome biogenesis disorder 4B. Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.17 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 26387595; 16530715
Amelogenesis imperfecta v2.16 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: The review by Claire Smith (University of Leeds)(below), states that amelogenesis imperfecta maybe over looked in patients with Peroxisome biogenesis disorder 4A (Zellweger) (OMIM:614862) and Peroxisome biogenesis disorder 4B (OMIM:6148630), as these conditions are characterized by a severe phenotype and premature death in some cases. With this in mind the Peroxisome biogenesis disorder 4B (OMIM:614863) could be relevant to this panel and such the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in order to detect variants resulting in allelic expression imbalance and dominant-negative effect (PMID: 29220678).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.16 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Heimler syndrome 2, OMIM:616617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.16 LTBP3 Eleanor Williams changed review comment from: Leaving the mode of inheritance as Biallelic. Cases reporting a dental phenotype have all had biallelic variants.
Monoallelic cases have also been reported with geleophysic dysplasia and acromelic dysplasia and therefore the mode of inheritance on the skeletal dysplasia panel covers both mode of inheritance.; to: Leaving the mode of inheritance as Biallelic. Cases reporting a dental phenotype have all had biallelic variants.

Monoallelic cases have also been reported with geleophysic dysplasia and acromelic dysplasia phenotypes and therefore the mode of inheritance on the skeletal dysplasia panel covers both mode of inheritance.
Amelogenesis imperfecta v2.16 LTBP3 Eleanor Williams commented on gene: LTBP3
Amelogenesis imperfecta v2.16 LTBP3 Eleanor Williams Publications for gene: LTBP3 were set to 25669657; 28084688
Amelogenesis imperfecta v2.15 LTBP3 Eleanor Williams Phenotypes for gene: LTBP3 were changed from Dental anomalies and short stature, 601216; Amelogenesis Imperfecta; syndromic AI with brachyolmia to Dental anomalies and short stature, OMIM:601216; Amelogenesis Imperfecta; syndromic AI with brachyolmia
Amelogenesis imperfecta v2.14 PEX26 Eleanor Williams Classified gene: PEX26 as Amber List (moderate evidence)
Amelogenesis imperfecta v2.14 PEX26 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber for now, but with recommendation for green rating following GMS review. 3 cases now reported with a syndromic amelogenesis imperfecta phenotype.
Amelogenesis imperfecta v2.14 PEX26 Eleanor Williams Gene: pex26 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v2.13 PEX26 Eleanor Williams Phenotypes for gene: PEX26 were changed from Peroxisome biogenesis disorder 7A (Zellweger), 614872; Peroxisome biogenesis disorder 7B, 614873; Heimler syndrome; Amelogenesis imperfecta; enamel dysplasia to Amelogenesis Imperfecta, MONDO:0019507; Heimler syndrome
Amelogenesis imperfecta v2.12 PEX26 Eleanor Williams Publications for gene: PEX26 were set to 28944237
Amelogenesis imperfecta v2.11 PEX26 Eleanor Williams Tag watchlist was removed from gene: PEX26.
Tag Q3_21_rating tag was added to gene: PEX26.
Amelogenesis imperfecta v2.11 PEX26 Eleanor Williams commented on gene: PEX26
Amelogenesis imperfecta v2.11 SP6 Eleanor Williams Classified gene: SP6 as Amber List (moderate evidence)
Amelogenesis imperfecta v2.11 SP6 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber, but with recommendation for green rating following GMS review. 2 unrelated cases, plus animal model.
Amelogenesis imperfecta v2.11 SP6 Eleanor Williams Gene: sp6 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v2.10 SP6 Eleanor Williams Phenotypes for gene: SP6 were changed from Amelogenesis Imperfecta to Amelogenesis Imperfecta, MONDO:0019507
Amelogenesis imperfecta v2.9 SP6 Eleanor Williams Publications for gene: SP6 were set to 32167558; 18156176; 18297738; 22676574
Amelogenesis imperfecta v2.8 SP6 Eleanor Williams Tag Q3_21_rating tag was added to gene: SP6.
Amelogenesis imperfecta v2.8 SP6 Eleanor Williams edited their review of gene: SP6: Added comment: Additional case from Korea reported in PMID: 33652941 (Kim et al 2021) has the same nucleotide positions affected as in previous case (c.817_818delinsAT, p.(Ala273Met)) in the SP6 gene. The variant was de novo and the child showed unusual root development, taurodontism, and severe hypoplastic AI.; Changed rating: GREEN
Amelogenesis imperfecta v2.8 SP6 Zornitza Stark reviewed gene: SP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33652941; Phenotypes: Amelogenesis imperfecta; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v2.8 PEX26 Zornitza Stark reviewed gene: PEX26: Rating: GREEN; Mode of pathogenicity: None; Publications: 33926089; Phenotypes: Heimler syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.8 DLX3 Eleanor Williams changed review comment from: Comment on phenotypes: Adding phenotype of Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic to this gene at suggestion of Dr Susan Parekh (Consultant in Pediatric Dentistry, GOSH); to: Comment on phenotypes: Adding phenotype of Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic to this gene at suggestion of Dr Susan Parekh (Consultant in Pediatric Dentistry, GOSH)
Amelogenesis imperfecta v2.8 SP6 Eleanor Williams Publications for gene: SP6 were set to 32167558
Amelogenesis imperfecta v2.7 SP6 Eleanor Williams Classified gene: SP6 as Amber List (moderate evidence)
Amelogenesis imperfecta v2.7 SP6 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber. 1 case plus rodent models reported.
Amelogenesis imperfecta v2.7 SP6 Eleanor Williams Gene: sp6 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v2.6 SP6 Eleanor Williams gene: SP6 was added
gene: SP6 was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: SP6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP6 were set to 32167558
Phenotypes for gene: SP6 were set to Amelogenesis Imperfecta
Review for gene: SP6 was set to AMBER
Added comment: PMID: 32167558 - Smith et al 2020 - report a 2 bp variant c.817_818GC>AA in SP6 in a Caucasian family with autosomal dominant hypoplastic AI which results in a missense change. Report that mice and rat knockouts also show a dental phenotype (PMID: 18156176, 18297738, 22676574 )
Sources: Literature
Amelogenesis imperfecta v2.5 AMELX Eleanor Williams Phenotypes for gene: AMELX were changed from Amelogenesis imperfecta, type 1E, 301200; Amelogenesis Imperfecta, Type IE, 301200; X-linked hypoplastic amelogenesis imperfecta; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI to Amelogenesis imperfecta, type 1E, 301200; iX-linked hypoplastic amelogenesis imperfecta; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI
Amelogenesis imperfecta v2.4 Eleanor Williams Panel version has been signed off
Amelogenesis imperfecta v2.3 Eleanor Williams Panel version has been signed off
Amelogenesis imperfecta v2.2 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Amelogenesis imperfecta v2.0 PEX6 Louise Daugherty Tag watchlist was removed from gene: PEX6.
Amelogenesis imperfecta v2.0 PEX6 Louise Daugherty commented on gene: PEX6
Amelogenesis imperfecta v2.0 Eleanor Williams promoted panel to version 2.0
Amelogenesis imperfecta v1.17 Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Amelogenesis imperfecta v1.16 Eleanor Williams List of related panels changed from Amelogenesis Imperfecta to Amelogenesis Imperfecta; R340
Amelogenesis imperfecta v1.14 DLX3 Eleanor Williams Added comment: Comment on phenotypes: Adding phenotype of Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic to this gene at suggestion of Dr Susan Parekh (Consultant in Pediatric Dentistry, GOSH)
Amelogenesis imperfecta v1.14 DLX3 Eleanor Williams Phenotypes for gene: DLX3 were changed from Amelogenesis imperfecta, type IV, 104510; Amelogenesis Imperfecta, Type IV, 104510; Amelogenesis Imperfecta, Dominant; amelogenesis imperfecta with taurodontism; Trichodontoosseous syndrome, 190320; Tricho-dento-osseous syndrome (TDO) (includes enamel hypoplasia); hypoplastic AI, taurodontism and kinky hair to Amelogenesis imperfecta, type IV, 104510; Amelogenesis Imperfecta, Type IV, 104510; Amelogenesis Imperfecta, Dominant; amelogenesis imperfecta with taurodontism; Trichodontoosseous syndrome, 190320; Tricho-dento-osseous syndrome (TDO) (includes enamel hypoplasia); hypoplastic AI, taurodontism and kinky hair; Tricho-Dento-Osseous syndrome , Amelogenesis Imperfecta, hypoplastic
Amelogenesis imperfecta v1.13 RELT Eleanor Williams Phenotypes for gene: RELT were changed from amelogenesis imperfecta (hypoplastic) to amelogenesis imperfecta (hypoplastic); Amelogenesis imperfecta, type IIIC, 618386
Amelogenesis imperfecta v1.12 SLC10A7 Eleanor Williams Phenotypes for gene: SLC10A7 were changed from skeletal dysplasia and amelogenesis imperfecta to skeletal dysplasia and amelogenesis imperfecta; Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS) 618363; short stature; amelogenesis imperfect hypo mineralised; skeletal dysplasia; scoliosis
Amelogenesis imperfecta v1.11 SLC10A7 Eleanor Williams Publications for gene: SLC10A7 were set to 30082715
Amelogenesis imperfecta v1.10 SLC10A7 Eleanor Williams Classified gene: SLC10A7 as Green List (high evidence)
Amelogenesis imperfecta v1.10 SLC10A7 Eleanor Williams Added comment: Comment on list classification: Upgrading to green as the are now 5 distinct families with identified variants in SLC10A7 and a relevant phenotype. Evidence also from zebrafish and mouse models.
Amelogenesis imperfecta v1.10 SLC10A7 Eleanor Williams Gene: slc10a7 has been classified as Green List (High Evidence).
Amelogenesis imperfecta v1.9 SLC10A7 Eleanor Williams commented on gene: SLC10A7
Amelogenesis imperfecta v1.9 SLC10A7 Claire Smith reviewed gene: SLC10A7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29878199, 30082715; Phenotypes: OMIM: 618363 Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS), short stature, amelogenesis imperfect hypo mineralised, skeletal dysplasia, scoliosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v1.9 RELT Eleanor Williams Publications for gene: RELT were set to PMID: 30506946
Amelogenesis imperfecta v1.8 RELT Eleanor Williams Classified gene: RELT as Green List (high evidence)
Amelogenesis imperfecta v1.8 RELT Eleanor Williams Added comment: Comment on list classification: 3 cases with 3 different variants. Segregation of the variant with the disease. Mouse knockout shows a related phenotype.
Amelogenesis imperfecta v1.8 RELT Eleanor Williams Gene: relt has been classified as Green List (High Evidence).
Amelogenesis imperfecta v1.7 RELT Eleanor Williams commented on gene: RELT
Amelogenesis imperfecta v1.7 RELT Claire Smith gene: RELT was added
gene: RELT was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: RELT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RELT were set to PMID: 30506946
Phenotypes for gene: RELT were set to amelogenesis imperfecta (hypoplastic)
Penetrance for gene: RELT were set to Complete
Review for gene: RELT was set to GREEN
Added comment: PMID: 30506946 present evidence of three consanguineous Turkish families with irregular hypoplastic amelogenesis imperfecta. The authors also present a Relt-/- mouse model with incisor and molar enamel malformations. RELT should be included as a causative gene in diagnostic panels for AR AI in future.
Sources: Literature
Amelogenesis imperfecta v1.6 Ellen McDonagh Panel name changed from Amelogenesis Imperfecta to Amelogenesis imperfecta
List of related panels changed from to Amelogenesis Imperfecta
Panel types changed to Rare Disease 100K; GMS Rare Disease
Amelogenesis imperfecta v1.5 SLC10A7 Ellen McDonagh gene: SLC10A7 was added
gene: SLC10A7 was added to Amelogenesis Imperfecta. Sources: Literature
Mode of inheritance for gene: SLC10A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC10A7 were set to 30082715
Phenotypes for gene: SLC10A7 were set to skeletal dysplasia and amelogenesis imperfecta
Added comment: PMID: 30082715 reports five different SLC10A7 variants in four patients from four unrelated families and two patients from two distantly related families. The study states that the variants segregated according to a recessive mode of inheritance, however the genotype was not shown on the pedigree diagram. Further evidence was provided in a knockout mouse model that displayed abnormal development of skeletal structures and teeth anomalies. This gene is not related to a disease in OMIM or Gene2Phenotype.
Sources: Literature
Amelogenesis imperfecta Sarah Leigh promoted panel to version 1.0
Amelogenesis imperfecta CLDN16 Sarah Leigh classified CLDN16 as Amber List (moderate evidence)
Amelogenesis imperfecta CLDN16 Sarah Leigh marked CLDN16 as ready
Amelogenesis imperfecta CLDN19 Sarah Leigh marked CLDN19 as ready
Amelogenesis imperfecta CLDN19 Sarah Leigh classified CLDN19 as Amber List (moderate evidence)
Amelogenesis imperfecta LTBP3 Sarah Leigh marked LTBP3 as ready
Amelogenesis imperfecta SLC13A5 Sarah Leigh marked SLC13A5 as ready
Amelogenesis imperfecta SLC13A5 Sarah Leigh classified SLC13A5 as Green List (high evidence)
Amelogenesis imperfecta TUFT1 Sarah Leigh reviewed TUFT1
Amelogenesis imperfecta ROGDI Sarah Leigh marked ROGDI as ready
Amelogenesis imperfecta ROGDI Sarah Leigh classified ROGDI as Green List (high evidence)
Amelogenesis imperfecta ORAI1 Sarah Leigh marked ORAI1 as ready
Amelogenesis imperfecta ORAI1 Sarah Leigh classified ORAI1 as Green List (high evidence)
Amelogenesis imperfecta STIM1 Sarah Leigh marked STIM1 as ready
Amelogenesis imperfecta PEX26 Ellen McDonagh marked PEX26 as ready
Amelogenesis imperfecta STIM1 Ellen McDonagh marked STIM1 as ready
Amelogenesis imperfecta SLC13A5 Claire Smith reviewed SLC13A5
Amelogenesis imperfecta STIM1 Claire Smith reviewed STIM1
Amelogenesis imperfecta ROGDI Claire Smith reviewed ROGDI
Amelogenesis imperfecta COL17A1 Claire Smith reviewed COL17A1
Amelogenesis imperfecta ORAI1 Claire Smith reviewed ORAI1
Amelogenesis imperfecta LAMB3 Rebecca Foulger marked LAMB3 as ready
Amelogenesis imperfecta LAMA3 Rebecca Foulger marked LAMA3 as ready
Amelogenesis imperfecta COL17A1 Rebecca Foulger marked COL17A1 as ready
Amelogenesis imperfecta AMTN Rebecca Foulger classified AMTN as amber
Amelogenesis imperfecta PEX26 Rebecca Foulger classified PEX26 as amber
Amelogenesis imperfecta PEX26 Rebecca Foulger edited their review of PEX26
Amelogenesis imperfecta PEX26 Rebecca Foulger commented on PEX26
Amelogenesis imperfecta PEX1 Rebecca Foulger marked PEX1 as ready
Amelogenesis imperfecta PEX6 Rebecca Foulger marked PEX6 as ready
Amelogenesis imperfecta PEX6 Rebecca Foulger classified PEX6 as green
Amelogenesis imperfecta STIM1 Rebecca Foulger classified STIM1 as green
Amelogenesis imperfecta STIM1 Rebecca Foulger commented on STIM1
Amelogenesis imperfecta STIM1 Rebecca Foulger edited their review of STIM1
Amelogenesis imperfecta STIM1 Rebecca Foulger commented on STIM1
Amelogenesis imperfecta PEX26 Claire Smith added PEX26 to panel
Amelogenesis imperfecta PEX26 Claire Smith reviewed PEX26
Amelogenesis imperfecta PEX1 Claire Smith reviewed PEX1
Amelogenesis imperfecta PEX6 Claire Smith reviewed PEX6
Amelogenesis imperfecta PEX6 Rebecca Foulger classified PEX6 as amber
Amelogenesis imperfecta PEX6 Rebecca Foulger commented on PEX6
Amelogenesis imperfecta PEX1 Rebecca Foulger classified PEX1 as green
Amelogenesis imperfecta PEX1 Rebecca Foulger commented on PEX1
Amelogenesis imperfecta PEX1 Rebecca Foulger commented on PEX1
Amelogenesis imperfecta PEX1 Rebecca Foulger commented on PEX1
Amelogenesis imperfecta ITGB4 Rebecca Foulger classified ITGB4 as amber
Amelogenesis imperfecta ITGB4 Rebecca Foulger commented on ITGB4
Amelogenesis imperfecta ITGB4 Rebecca Foulger edited their review of ITGB4
Amelogenesis imperfecta LTBP3 Rebecca Foulger classified LTBP3 as green
Amelogenesis imperfecta LTBP3 Rebecca Foulger commented on LTBP3
Amelogenesis imperfecta SLC24A4 Rebecca Foulger marked SLC24A4 as ready
Amelogenesis imperfecta SLC24A4 Rebecca Foulger classified SLC24A4 as green
Amelogenesis imperfecta SLC24A4 Rebecca Foulger commented on SLC24A4
Amelogenesis imperfecta SLC24A4 Rebecca Foulger edited their review of SLC24A4
Amelogenesis imperfecta SLC24A4 Rebecca Foulger commented on SLC24A4
Amelogenesis imperfecta COL17A1 Rebecca Foulger classified COL17A1 as green
Amelogenesis imperfecta COL17A1 Rebecca Foulger commented on COL17A1
Amelogenesis imperfecta COL17A1 Rebecca Foulger commented on COL17A1
Amelogenesis imperfecta COL17A1 Rebecca Foulger commented on COL17A1
Amelogenesis imperfecta LAMC2 Rebecca Foulger classified LAMC2 as amber
Amelogenesis imperfecta FAM20C Rebecca Foulger marked FAM20C as ready
Amelogenesis imperfecta FAM20C Rebecca Foulger classified FAM20C as green
Amelogenesis imperfecta FAM20C Rebecca Foulger classified FAM20C as red
Amelogenesis imperfecta FAM20C Rebecca Foulger commented on FAM20C
Amelogenesis imperfecta LAMB3 Rebecca Foulger marked LAMB3 as ready
Amelogenesis imperfecta GPR68 Rebecca Foulger marked GPR68 as ready
Amelogenesis imperfecta ACPT Rebecca Foulger marked ACPT as ready
Amelogenesis imperfecta FAM83H Rebecca Foulger marked FAM83H as ready
Amelogenesis imperfecta LAMC2 Rebecca Foulger marked LAMC2 as ready
Amelogenesis imperfecta LAMC2 Rebecca Foulger classified LAMC2 as red
Amelogenesis imperfecta CNNM4 emma baple marked CNNM4 as ready
Amelogenesis imperfecta CNNM4 emma baple classified CNNM4 as green
Amelogenesis imperfecta CNNM4 emma baple reviewed CNNM4
Amelogenesis imperfecta LAMA3 Rebecca Foulger marked LAMA3 as ready
Amelogenesis imperfecta LAMA3 Rebecca Foulger classified LAMA3 as green
Amelogenesis imperfecta FAM20C Claire Smith reviewed FAM20C
Amelogenesis imperfecta LAMC2 Claire Smith reviewed LAMC2
Amelogenesis imperfecta CNNM4 Claire Smith reviewed CNNM4
Amelogenesis imperfecta C4orf26 Louise Daugherty commented on C4orf26
Amelogenesis imperfecta AMBN Rebecca Foulger marked AMBN as ready
Amelogenesis imperfecta AMBN Rebecca Foulger edited their review of AMBN
Amelogenesis imperfecta AMBN Rebecca Foulger classified AMBN as green
Amelogenesis imperfecta GPR68 Rebecca Foulger edited their review of GPR68
Amelogenesis imperfecta GPR68 Rebecca Foulger classified GPR68 as green
Amelogenesis imperfecta GPR68 Rebecca Foulger commented on GPR68
Amelogenesis imperfecta LAMA3 Rebecca Foulger commented on LAMA3
Amelogenesis imperfecta LAMA3 Rebecca Foulger commented on LAMA3
Amelogenesis imperfecta LAMA3 Rebecca Foulger commented on LAMA3
Amelogenesis imperfecta LAMA3 Rebecca Foulger commented on LAMA3
Amelogenesis imperfecta ITGB6 Rebecca Foulger marked ITGB6 as ready
Amelogenesis imperfecta ITGB6 Rebecca Foulger classified ITGB6 as green
Amelogenesis imperfecta AMTN Rebecca Foulger marked AMTN as ready
Amelogenesis imperfecta AMTN Rebecca Foulger classified AMTN as red
Amelogenesis imperfecta AMBN Rebecca Foulger classified AMBN as amber
Amelogenesis imperfecta AMBN Rebecca Foulger commented on AMBN
Amelogenesis imperfecta ACPT Rebecca Foulger classified ACPT as green
Amelogenesis imperfecta ACPT Rebecca Foulger commented on ACPT
Amelogenesis imperfecta ACPT Rebecca Foulger commented on ACPT
Amelogenesis imperfecta ACPT Rebecca Foulger commented on ACPT
Amelogenesis imperfecta LAMB3 Rebecca Foulger classified LAMB3 as green
Amelogenesis imperfecta LAMB3 Rebecca Foulger commented on LAMB3
Amelogenesis imperfecta KLK4 Rebecca Foulger marked KLK4 as ready
Amelogenesis imperfecta KLK4 Rebecca Foulger classified KLK4 as green
Amelogenesis imperfecta KLK4 Rebecca Foulger commented on KLK4
Amelogenesis imperfecta FAM83H Rebecca Foulger marked FAM83H as ready
Amelogenesis imperfecta FAM83H Rebecca Foulger classified FAM83H as green
Amelogenesis imperfecta FAM83H Rebecca Foulger commented on FAM83H
Amelogenesis imperfecta FAM20A Rebecca Foulger marked FAM20A as ready
Amelogenesis imperfecta FAM20A Rebecca Foulger classified FAM20A as green
Amelogenesis imperfecta WDR72 Rebecca Foulger marked WDR72 as ready
Amelogenesis imperfecta WDR72 Rebecca Foulger classified WDR72 as green
Amelogenesis imperfecta WDR72 Rebecca Foulger commented on WDR72
Amelogenesis imperfecta MMP20 Rebecca Foulger marked MMP20 as ready
Amelogenesis imperfecta C4orf26 Rebecca Foulger marked C4orf26 as ready
Amelogenesis imperfecta C4orf26 Rebecca Foulger classified C4orf26 as green
Amelogenesis imperfecta ITGB6 Claire Smith reviewed ITGB6
Amelogenesis imperfecta SLC24A4 Claire Smith reviewed SLC24A4
Amelogenesis imperfecta LAMA3 Claire Smith reviewed LAMA3
Amelogenesis imperfecta AMTN Claire Smith reviewed AMTN
Amelogenesis imperfecta GPR68 Claire Smith reviewed GPR68
Amelogenesis imperfecta AMBN Claire Smith reviewed AMBN
Amelogenesis imperfecta ACPT Claire Smith reviewed ACPT
Amelogenesis imperfecta LAMB3 Claire Smith reviewed LAMB3
Amelogenesis imperfecta KLK4 Claire Smith reviewed KLK4
Amelogenesis imperfecta FAM83H Claire Smith reviewed FAM83H
Amelogenesis imperfecta FAM20A Claire Smith reviewed FAM20A
Amelogenesis imperfecta C4orf26 Claire Smith reviewed C4orf26
Amelogenesis imperfecta MMP20 Rebecca Foulger commented on MMP20
Amelogenesis imperfecta ENAM Rebecca Foulger marked ENAM as ready
Amelogenesis imperfecta ENAM Rebecca Foulger classified ENAM as green
Amelogenesis imperfecta DLX3 Rebecca Foulger marked DLX3 as ready
Amelogenesis imperfecta DLX3 Rebecca Foulger classified DLX3 as green
Amelogenesis imperfecta AMELX Rebecca Foulger marked AMELX as ready
Amelogenesis imperfecta AMELX Rebecca Foulger edited their review of AMELX
Amelogenesis imperfecta AMELX Rebecca Foulger classified AMELX as green
Amelogenesis imperfecta AMELX Rebecca Foulger commented on AMELX
Amelogenesis imperfecta AMELX Claire Smith reviewed AMELX
Amelogenesis imperfecta WDR72 Claire Smith reviewed WDR72
Amelogenesis imperfecta MMP20 Claire Smith reviewed MMP20
Amelogenesis imperfecta ACPT Louise Daugherty commented on ACPT
Amelogenesis imperfecta DLX3 Rebecca Foulger commented on DLX3
Amelogenesis imperfecta ENAM Claire Smith reviewed ENAM
Amelogenesis imperfecta DLX3 Claire Smith reviewed DLX3
Amelogenesis imperfecta TP63 Rebecca Foulger commented on TP63
Amelogenesis imperfecta KCNJ1 Rebecca Foulger commented on KCNJ1
Amelogenesis imperfecta AMTN Rebecca Foulger commented on AMTN
Amelogenesis imperfecta CLDN19 Rebecca Foulger commented on CLDN19
Amelogenesis imperfecta CLDN16 Rebecca Foulger commented on CLDN16
Amelogenesis imperfecta SLC13A5 Rebecca Foulger commented on SLC13A5
Amelogenesis imperfecta TMEM165 Rebecca Foulger commented on TMEM165
Amelogenesis imperfecta SMARCD2 Rebecca Foulger commented on SMARCD2
Amelogenesis imperfecta ROGDI Rebecca Foulger commented on ROGDI
Amelogenesis imperfecta C4orf26 Rebecca Foulger commented on C4orf26
Amelogenesis imperfecta COL17A1 Rebecca Foulger commented on COL17A1
Amelogenesis imperfecta FAM20C Rebecca Foulger commented on FAM20C
Amelogenesis imperfecta LAMC2 Rebecca Foulger edited their review of LAMC2
Amelogenesis imperfecta LAMC2 Rebecca Foulger commented on LAMC2
Amelogenesis imperfecta LAMA3 Rebecca Foulger edited their review of LAMA3
Amelogenesis imperfecta LAMA3 Rebecca Foulger commented on LAMA3
Amelogenesis imperfecta ITGB6 Rebecca Foulger commented on ITGB6
Amelogenesis imperfecta ITGB4 Rebecca Foulger commented on ITGB4
Amelogenesis imperfecta FAM20A Rebecca Foulger commented on FAM20A
Amelogenesis imperfecta ENAM Rebecca Foulger commented on ENAM
Amelogenesis imperfecta Ellen McDonagh approved panel