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Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407).

COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).

COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).

COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407).

COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).; to: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).

COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska changed review comment from: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia - no skeletal issues noted in PMID: 37734708. Hence, the MOI should remain MONOALLELIC, until more evidence emerges.; to: Comment on mode of inheritance: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia - no skeletal issues noted in PMID: 37734708. Hence, the MOI should remain MONOALLELIC, until more evidence emerges.
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska commented on gene: COPB2: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia - no skeletal issues noted in PMID: 37734708. Hence, the MOI should remain MONOALLELIC, until more evidence emerges.
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska Tag watchlist_moi was removed from gene: COPB2.
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska edited their review of gene: COPB2: Changed publications to: 29036432, 37734708
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.; to: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American proband reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.; to: PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.
Osteogenesis imperfecta v6.8 COPB2 Ida Ertmanska reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37734708; Phenotypes: Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884, ?Microcephaly 19, primary, autosomal recessive, OMIM:617800, microcephaly 19, primary, autosomal recessive, MONDO:0054716, osteoporosis, childhood- or juvenile-onset, with developmental delay, MONDO:0859253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Osteogenesis imperfecta v3.5 COPB2 Eleanor Williams Tag Q3_21_rating was removed from gene: COPB2.
Osteogenesis imperfecta v3.5 COPB2 Eleanor Williams commented on gene: COPB2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Osteogenesis imperfecta v3.4 COPB2 Eleanor Williams Source Expert Review Green was added to COPB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Osteogenesis imperfecta v2.37 COPB2 Eleanor Williams Classified gene: COPB2 as Amber List (moderate evidence)
Osteogenesis imperfecta v2.37 COPB2 Eleanor Williams Added comment: Comment on list classification: Leaving as amber for now, but there are 2 cases with fractures and 4 with osteopaenia, plus a mouse model with low bone mass, so sufficient to rate green after then next GMS review.
Osteogenesis imperfecta v2.37 COPB2 Eleanor Williams Gene: copb2 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.36 COPB2 Eleanor Williams Tag watchlist_moi tag was added to gene: COPB2.
Osteogenesis imperfecta v2.33 COPB2 Eleanor Williams Added comment: Comment on mode of inheritance: Left as monoallelic for now as only 1 biallelic case reported.
Osteogenesis imperfecta v2.33 COPB2 Eleanor Williams Mode of inheritance for gene: COPB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Osteogenesis imperfecta v2.29 COPB2 Eleanor Williams changed review comment from: As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass; to: As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2 +/-mice exhibit low bone mass.

PMID: 29036432 - original report of microcephaly in the two siblings with the COPB2 homozygous variant.
Osteogenesis imperfecta v2.29 COPB2 Eleanor Williams Publications for gene: COPB2 were set to 34450031
Osteogenesis imperfecta v2.28 COPB2 Eleanor Williams Phenotypes for gene: COPB2 were changed from juvenile osteoporosis to juvenile osteoporosis; Osteopenia; Osteoporosis; recurrent fractures
Osteogenesis imperfecta v2.27 COPB2 Eleanor Williams Publications for gene: COPB2 were set to Marom et al 2018 ASBMR: COPB2 Loss of Function Leads to Disrupted Collagen Trafficking and Juvenile Osteoporosis
Osteogenesis imperfecta v2.26 COPB2 Eleanor Williams Tag Q3_21_rating tag was added to gene: COPB2.
Osteogenesis imperfecta v2.26 COPB2 Eleanor Williams edited their review of gene: COPB2: Added comment: As Zornitza Stark reports, PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass; Changed rating: GREEN; Changed publications to: 34450031; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Osteogenesis imperfecta v2.23 COPB2 Zornitza Stark reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34450031; Phenotypes: Osteoporosis, recurrent fractures and developmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Osteogenesis imperfecta v1.47 COPB2 Eleanor Williams Classified gene: COPB2 as Amber List (moderate evidence)
Osteogenesis imperfecta v1.47 COPB2 Eleanor Williams Added comment: Comment on list classification: Following discussion in the GMS musculoskeletal specialist test group Webex on 2019-06-04 it was decided to make this gene amber.
Osteogenesis imperfecta v1.47 COPB2 Eleanor Williams Gene: copb2 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v1.19 COPB2 Duncan Baker edited their review of gene: COPB2: Added comment: Request from Dr Meena Balasubramian - plausible to cause bone fragility, add to panel if possible; Changed phenotypes: Juvenile Osteoporosis
Osteogenesis imperfecta v1.18 COPB2 Eleanor Williams edited their review of gene: COPB2: Added comment: This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: COPB2; Suggested initial gene rating: amber; Changed rating: AMBER
Osteogenesis imperfecta v1.17 COPB2 Eleanor Williams commented on gene: COPB2
Osteogenesis imperfecta v1.17 COPB2 Eleanor Williams Source NHS GMS was added to COPB2.
Rating Changed from No List (delete) to Red List (low evidence)
Osteogenesis imperfecta v1.16 COPB2 Duncan Baker gene: COPB2 was added
gene: COPB2 was added to Osteogenesis imperfecta. Sources: Expert list
Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COPB2 were set to Marom et al 2018 ASBMR: COPB2 Loss of Function Leads to Disrupted Collagen Trafficking and Juvenile Osteoporosis
Phenotypes for gene: COPB2 were set to juvenile osteoporosis
Review for gene: COPB2 was set to AMBER
Added comment: New gene. One report linking to juvenile osteoporosis
Sources: Expert list