Entry - #611755 - LEBER CONGENITAL AMAUROSIS 10; LCA10 - OMIM
# 611755

LEBER CONGENITAL AMAUROSIS 10; LCA10


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
12q21.32 Leber congenital amaurosis 10 611755 3 CEP290 610142
Phenotypic Series
 

Leber congenital amaurosis - PS204000 - 26 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p36.22 Leber congenital amaurosis 9 AR 3 608553 NMNAT1 608700
1p31.3 Leber congenital amaurosis 2 AR 3 204100 RPE65 180069
1q31.3 Leber congenital amaurosis 8 AR 3 613835 CRB1 604210
1q32.3 Leber congenital amaurosis 12 AR 3 610612 RD3 180040
2q37.1 Leber congenital amaurosis 16 AR 3 614186 KCNJ13 603208
4q32.1 Retinitis pigmentosa, juvenile AR 3 613341 LRAT 604863
4q32.1 Retinal dystrophy, early-onset severe AR 3 613341 LRAT 604863
4q32.1 Leber congenital amaurosis 14 AR 3 613341 LRAT 604863
6p21.31 Leber congenital amaurosis 15 AR 3 613843 TULP1 602280
6p21.1 Retinitis pigmentosa 7 and digenic form AD, AR, DD 3 608133 PRPH2 179605
6p21.1 Leber congenital amaurosis 18 AD, AR, DD 3 608133 PRPH2 179605
6q14.1 Leber congenital amaurosis 5 AR 3 604537 LCA5 611408
6q16.2 ?Leber congenital amaurosis 19 AR 3 618513 USP45 618439
7q32.1 Leber congenital amaurosis 11 AD 3 613837 IMPDH1 146690
8q22.1 Leber congenital amaurosis 17 AR 3 615360 GDF6 601147
11q12.3 Retinitis pigmentosa 7, digenic form AD, AR, DD 3 608133 ROM1 180721
12q21.32 Leber congenital amaurosis 10 3 611755 CEP290 610142
14q11.2 Leber congenital amaurosis 6 AR 3 613826 RPGRIP1 605446
14q24.1 Leber congenital amaurosis 13 AD, AR 3 612712 RDH12 608830
14q31.3 Retinitis pigmentosa 94, variable age at onset, autosomal recessive AR 3 604232 SPATA7 609868
14q31.3 Leber congenital amaurosis 3 AR 3 604232 SPATA7 609868
17p13.2 Cone-rod dystrophy AD, AR 3 604393 AIPL1 604392
17p13.2 Retinitis pigmentosa, juvenile AD, AR 3 604393 AIPL1 604392
17p13.2 Leber congenital amaurosis 4 AD, AR 3 604393 AIPL1 604392
17p13.1 Leber congenital amaurosis 1 AR 3 204000 GUCY2D 600179
19q13.33 Leber congenital amaurosis 7 3 613829 CRX 602225

TEXT

A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-10 (LCA10) is caused by homozygous or compound heterozygous mutations in the CEP290 gene (610142) on chromosome 12q21.


Description

Leber congenital amaurosis (LCA) is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life (summary by den Hollander et al., 2006).

For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000).


Clinical Features

Den Hollander et al. (2006) reported a consanguineous French Canadian family in which 4 sibs had Leber congenital amaurosis. The sibs were blind or severely visually impaired at birth. Two of the 4 experienced seizures but had no other neurologic symptoms. All 4 had normal cognitive function. Detailed CT scanning revealed no molar-tooth sign, no cerebellar atrophy, and no structural signs of Joubert syndrome (see 213300).

McEwen et al. (2007) found that affected individuals from the family reported by den Hollander et al. (2006) had severely impaired olfactory function, whereas heterozygous mutation carriers had mild to severe microsomia. They noted that all patients queried before testing reported self-assumed normal olfactory functioning. They postulated that olfactory dysfunction may be prevalent in patients with ciliary diseases.

Using in vivo microscopy of the central retina and colocalized rod and cone vision, Cideciyan et al. (2007) found that patients with LCA10 due to mutations in the CEP290 gene retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. Foveal cones were preserved, and visual brain pathways were anatomically intact. Despite severe blindness and rapid rod cell death, the findings suggested an opportunity for visual restoration of central vision.

Papon et al. (2010) studied the otorhinolaryngologic phenotype and examined nasal cilia of 7 LCA patients from 6 families with known CEP290 mutations. In 5 of 7 cases, electron microscopy could be performed, which revealed high levels of respiratory cilia defects, involving the dynein arms, central complex, and/or peripheral microtubules. All patients had rarefaction of ciliated cells and a variable proportion of short cilia. Frequent but moderate and heterogeneous clinical and ciliary beating abnormalities were found. CEP290 was highly expressed in neural retina and nasal epithelial cells compared to other tissues. Papon et al. (2010) suggested that the presence of respiratory symptoms in LCA patients might represent additional clinical criteria for CEP290 genotyping.


Inheritance

The transmission pattern of LCA10 in the families reported by den Hollander et al. (2006) was consistent with autosomal recessive inheritance.


Clinical Management

Gene Therapy

Pierce et al. (2024) performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with LCA10 caused by a homozygous or compound heterozygous CEP290 intron 26 variant (610142.0005) received a subretinal injection of EDIT-101, a CRISPR-Cas9 gene editing complex designed to treat this specific damaging variant, in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality of life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children). EDIT-101 was injected in 12 adults aged 17 to 63 years (median, 37 years) at a low, intermediate, or high dose, and in 2 children aged 9 and 14 years at the intermediate dose. No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least 1 other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.


Mapping

Using linkage analysis, den Hollander et al. (2006) assigned the gene responsible for LCA in a consanguineous French Canadian family with 4 affected sibs to chromosome 12q21-q22, in a region containing 15 genes, including CEP290 (610142). Joubert syndrome-5 (610188), which is due to mutations in the CEP290 gene, is associated in all patients with congenital amaurosis or retinitis pigmentosa. An in-frame deletion in the Cep290 gene was found in association with early onset in the rd16 mouse (Chang et al., 2006). After extensive evaluation, no gross brain or kidney pathology could be detected in these mice.


Molecular Genetics

Because of the function of the CEP290 gene and the phenotype of the rd16 mice, den Hollander et al. (2006) considered CEP290 to be an excellent candidate gene for LCA10 in the French Canadian family. They sequenced all 53 coding exons and splice junctions and detected only 1 synonymous sequence variant in exon 21 that was not a known SNP. Since the variant was located between the splice donor site and a predicted exonic splice enhancer, den Hollander et al. (2006) reasoned that it may have an effect on the splicing of this exon. However, this could not be confirmed. Subsequent analysis of the complete CEP290 mRNA by RT-PCR revealed an aberrant splice product with insertion of a 128-bp cryptic exon between exons 26 and 27, which introduced a stop codon immediately downstream of exon 26. Sequencing of the genomic DNA surrounding the cryptic exon showed an A-to-G transition 5 bp downstream of the cryptic exon (2991+1655A-G; 610142.0005). The mutation created a strong splice donor site, which presumably led to efficient splicing of the cryptic exon into the CEP290 mRNA.

To determine whether this mutation could be a common cause of LCA10, den Hollander et al. (2006) screened 76 unrelated patients with LCA for the 2991+1655A-G mutation by allele-specific PCR. Four patients were found to be homozygous for the mutation, and 12 were heterozygous. The mutation was not detected in 223 French Canadian controls, and only 1 of 248 Dutch control individuals was found to be heterozygous for the mutation. Den Hollander et al. (2006) suggested that this mutation may account for up to 21% of LCA cases. Twelve patients who were heterozygous for 2991+1655A-G were analyzed for additional mutations in the 53 coding exons and splice junction of CEP290 by heteroduplex analysis and/or direct sequencing. In all patients, they detected a heterozygous mutation on the other allele.

In 9 LCA families in which 2 CEP290 mutations were identified by den Hollander et al. (2006), family members were available for segregation analysis. In all 9 families, segregation of the variants as expected for autosomal recessive inheritance was observed. The patients had no neurologic symptoms typical of Joubert syndrome, had normal cognitive function, and showed no clinical signs of renal disease. The patients studied by den Hollander et al. (2006) originated from various geographic regions, including Canada, Germany, the Netherlands, and Italy. The results suggested a complete loss of function of both CEP290 alleles leads to Joubert syndrome, whereas patients with LCA10 have a small amount of residual CEP290 activity.

In a patient with LCA10, Cideciyan et al. (2007) identified compound heterozygosity for 2 mutations in the CEP290 gene: the common splice site defect (610142.0005) and a 5-bp deletion (1260delTAAAG; 610142.0011).


REFERENCES

  1. Chang, B., Khanna, H., Hawes, N., Jimeno, D., He, S., Lillo, C., Parapuram, S. K., Cheng, H., Scott, A., Hurd, R. E., Sayer, J. A., Otto, E. A., Attanasio, M., O'Toole, J. F., Jin, G., Shou, C., Hildebrandt, F., Williams, D. S., Heckenlively, J. R., Swaroop, A. In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum. Molec. Genet. 15: 1847-1857, 2006. [PubMed: 16632484, images, related citations] [Full Text]

  2. Cideciyan, A. V., Aleman, T. S., Jacobson, S. G., Khanna, H., Sumaroka, A., Aguirre, G. K., Schwartz, S. B., Windsor, E. A. M., He, S., Chang, B., Stone, E. M., Swaroop, A. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum. Mutat. 28: 1074-1083, 2007. [PubMed: 17554762, related citations] [Full Text]

  3. den Hollander, A. I., Koenekoop, R. K., Yzer, S., Lopez, I., Arends, M. L., Voesenek, K. E. J., Zonneveld, M. N., Strom, T. M., Meitinger, T., Brunner, H. G., Hoyng, C. B., van den Born, L. I., Rohrschneider, K., Cremers, F. P. M. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am. J. Hum. Genet. 79: 556-561, 2006. [PubMed: 16909394, images, related citations] [Full Text]

  4. McEwen, D. P., Koenekoop, R. K., Khanna, H., Jenkins, P. M., Lopez, I., Swaroop, A., Martens, J. R. Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc. Nat. Acad. Sci. 104: 15917-15922, 2007. [PubMed: 17898177, images, related citations] [Full Text]

  5. Papon, J. F., Perrault, I., Coste, A., Louis, B., Gerard, X., Hanein, S., Fares-Taie, L., Gerber, S., Defoort-Dhellemmes, S., Vojtek, A. M., Kaplan, J., Rozet, J. M., Escudier, E. Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations. J. Med. Genet. 47: 829-834, 2010. [PubMed: 20805370, related citations] [Full Text]

  6. Pierce, E. A., Aleman, T. S., Jayasundera, K. T., Ashimatey, B. S., Kim, K., Rashid, A., Jaskolka, M. C., Myers, R. L., Lam, B. L., Bailey, S. T., Comander, J. I., Lauer, A. K., Maguire, A. M., Pennesi, M. E. Gene editing for CEP290-associated retinal degeneration. New Eng. J. Med. 390: 1972-1984, 2024. [PubMed: 38709228, related citations] [Full Text]


Ada Hamosh - updated : 06/07/2024
Marla J. F. O'Neill - updated : 3/2/2011
Cassandra L. Kniffin - updated : 1/31/2008
Cassandra L. Kniffin - updated : 1/29/2008
Creation Date:
Victor A. McKusick : 1/25/2008
alopez : 06/07/2024
carol : 04/26/2024
carol : 12/08/2016
carol : 12/08/2016
wwang : 03/03/2011
terry : 3/2/2011
carol : 4/3/2009
carol : 3/4/2008
ckniffin : 1/31/2008
wwang : 1/31/2008
ckniffin : 1/29/2008
ckniffin : 1/29/2008
alopez : 1/25/2008

# 611755

LEBER CONGENITAL AMAUROSIS 10; LCA10


ORPHA: 65;   DO: 0110291;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
12q21.32 Leber congenital amaurosis 10 611755 3 CEP290 610142

TEXT

A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-10 (LCA10) is caused by homozygous or compound heterozygous mutations in the CEP290 gene (610142) on chromosome 12q21.


Description

Leber congenital amaurosis (LCA) is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life (summary by den Hollander et al., 2006).

For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000).


Clinical Features

Den Hollander et al. (2006) reported a consanguineous French Canadian family in which 4 sibs had Leber congenital amaurosis. The sibs were blind or severely visually impaired at birth. Two of the 4 experienced seizures but had no other neurologic symptoms. All 4 had normal cognitive function. Detailed CT scanning revealed no molar-tooth sign, no cerebellar atrophy, and no structural signs of Joubert syndrome (see 213300).

McEwen et al. (2007) found that affected individuals from the family reported by den Hollander et al. (2006) had severely impaired olfactory function, whereas heterozygous mutation carriers had mild to severe microsomia. They noted that all patients queried before testing reported self-assumed normal olfactory functioning. They postulated that olfactory dysfunction may be prevalent in patients with ciliary diseases.

Using in vivo microscopy of the central retina and colocalized rod and cone vision, Cideciyan et al. (2007) found that patients with LCA10 due to mutations in the CEP290 gene retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. Foveal cones were preserved, and visual brain pathways were anatomically intact. Despite severe blindness and rapid rod cell death, the findings suggested an opportunity for visual restoration of central vision.

Papon et al. (2010) studied the otorhinolaryngologic phenotype and examined nasal cilia of 7 LCA patients from 6 families with known CEP290 mutations. In 5 of 7 cases, electron microscopy could be performed, which revealed high levels of respiratory cilia defects, involving the dynein arms, central complex, and/or peripheral microtubules. All patients had rarefaction of ciliated cells and a variable proportion of short cilia. Frequent but moderate and heterogeneous clinical and ciliary beating abnormalities were found. CEP290 was highly expressed in neural retina and nasal epithelial cells compared to other tissues. Papon et al. (2010) suggested that the presence of respiratory symptoms in LCA patients might represent additional clinical criteria for CEP290 genotyping.


Inheritance

The transmission pattern of LCA10 in the families reported by den Hollander et al. (2006) was consistent with autosomal recessive inheritance.


Clinical Management

Gene Therapy

Pierce et al. (2024) performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with LCA10 caused by a homozygous or compound heterozygous CEP290 intron 26 variant (610142.0005) received a subretinal injection of EDIT-101, a CRISPR-Cas9 gene editing complex designed to treat this specific damaging variant, in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality of life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children). EDIT-101 was injected in 12 adults aged 17 to 63 years (median, 37 years) at a low, intermediate, or high dose, and in 2 children aged 9 and 14 years at the intermediate dose. No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least 1 other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.


Mapping

Using linkage analysis, den Hollander et al. (2006) assigned the gene responsible for LCA in a consanguineous French Canadian family with 4 affected sibs to chromosome 12q21-q22, in a region containing 15 genes, including CEP290 (610142). Joubert syndrome-5 (610188), which is due to mutations in the CEP290 gene, is associated in all patients with congenital amaurosis or retinitis pigmentosa. An in-frame deletion in the Cep290 gene was found in association with early onset in the rd16 mouse (Chang et al., 2006). After extensive evaluation, no gross brain or kidney pathology could be detected in these mice.


Molecular Genetics

Because of the function of the CEP290 gene and the phenotype of the rd16 mice, den Hollander et al. (2006) considered CEP290 to be an excellent candidate gene for LCA10 in the French Canadian family. They sequenced all 53 coding exons and splice junctions and detected only 1 synonymous sequence variant in exon 21 that was not a known SNP. Since the variant was located between the splice donor site and a predicted exonic splice enhancer, den Hollander et al. (2006) reasoned that it may have an effect on the splicing of this exon. However, this could not be confirmed. Subsequent analysis of the complete CEP290 mRNA by RT-PCR revealed an aberrant splice product with insertion of a 128-bp cryptic exon between exons 26 and 27, which introduced a stop codon immediately downstream of exon 26. Sequencing of the genomic DNA surrounding the cryptic exon showed an A-to-G transition 5 bp downstream of the cryptic exon (2991+1655A-G; 610142.0005). The mutation created a strong splice donor site, which presumably led to efficient splicing of the cryptic exon into the CEP290 mRNA.

To determine whether this mutation could be a common cause of LCA10, den Hollander et al. (2006) screened 76 unrelated patients with LCA for the 2991+1655A-G mutation by allele-specific PCR. Four patients were found to be homozygous for the mutation, and 12 were heterozygous. The mutation was not detected in 223 French Canadian controls, and only 1 of 248 Dutch control individuals was found to be heterozygous for the mutation. Den Hollander et al. (2006) suggested that this mutation may account for up to 21% of LCA cases. Twelve patients who were heterozygous for 2991+1655A-G were analyzed for additional mutations in the 53 coding exons and splice junction of CEP290 by heteroduplex analysis and/or direct sequencing. In all patients, they detected a heterozygous mutation on the other allele.

In 9 LCA families in which 2 CEP290 mutations were identified by den Hollander et al. (2006), family members were available for segregation analysis. In all 9 families, segregation of the variants as expected for autosomal recessive inheritance was observed. The patients had no neurologic symptoms typical of Joubert syndrome, had normal cognitive function, and showed no clinical signs of renal disease. The patients studied by den Hollander et al. (2006) originated from various geographic regions, including Canada, Germany, the Netherlands, and Italy. The results suggested a complete loss of function of both CEP290 alleles leads to Joubert syndrome, whereas patients with LCA10 have a small amount of residual CEP290 activity.

In a patient with LCA10, Cideciyan et al. (2007) identified compound heterozygosity for 2 mutations in the CEP290 gene: the common splice site defect (610142.0005) and a 5-bp deletion (1260delTAAAG; 610142.0011).


REFERENCES

  1. Chang, B., Khanna, H., Hawes, N., Jimeno, D., He, S., Lillo, C., Parapuram, S. K., Cheng, H., Scott, A., Hurd, R. E., Sayer, J. A., Otto, E. A., Attanasio, M., O'Toole, J. F., Jin, G., Shou, C., Hildebrandt, F., Williams, D. S., Heckenlively, J. R., Swaroop, A. In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum. Molec. Genet. 15: 1847-1857, 2006. [PubMed: 16632484] [Full Text: https://doi.org/10.1093/hmg/ddl107]

  2. Cideciyan, A. V., Aleman, T. S., Jacobson, S. G., Khanna, H., Sumaroka, A., Aguirre, G. K., Schwartz, S. B., Windsor, E. A. M., He, S., Chang, B., Stone, E. M., Swaroop, A. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum. Mutat. 28: 1074-1083, 2007. [PubMed: 17554762] [Full Text: https://doi.org/10.1002/humu.20565]

  3. den Hollander, A. I., Koenekoop, R. K., Yzer, S., Lopez, I., Arends, M. L., Voesenek, K. E. J., Zonneveld, M. N., Strom, T. M., Meitinger, T., Brunner, H. G., Hoyng, C. B., van den Born, L. I., Rohrschneider, K., Cremers, F. P. M. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am. J. Hum. Genet. 79: 556-561, 2006. [PubMed: 16909394] [Full Text: https://doi.org/10.1086/507318]

  4. McEwen, D. P., Koenekoop, R. K., Khanna, H., Jenkins, P. M., Lopez, I., Swaroop, A., Martens, J. R. Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc. Nat. Acad. Sci. 104: 15917-15922, 2007. [PubMed: 17898177] [Full Text: https://doi.org/10.1073/pnas.0704140104]

  5. Papon, J. F., Perrault, I., Coste, A., Louis, B., Gerard, X., Hanein, S., Fares-Taie, L., Gerber, S., Defoort-Dhellemmes, S., Vojtek, A. M., Kaplan, J., Rozet, J. M., Escudier, E. Abnormal respiratory cilia in non-syndromic Leber congenital amaurosis with CEP290 mutations. J. Med. Genet. 47: 829-834, 2010. [PubMed: 20805370] [Full Text: https://doi.org/10.1136/jmg.2010.077883]

  6. Pierce, E. A., Aleman, T. S., Jayasundera, K. T., Ashimatey, B. S., Kim, K., Rashid, A., Jaskolka, M. C., Myers, R. L., Lam, B. L., Bailey, S. T., Comander, J. I., Lauer, A. K., Maguire, A. M., Pennesi, M. E. Gene editing for CEP290-associated retinal degeneration. New Eng. J. Med. 390: 1972-1984, 2024. [PubMed: 38709228] [Full Text: https://doi.org/10.1056/NEJMoa2309915]


Contributors:
Ada Hamosh - updated : 06/07/2024
Marla J. F. O'Neill - updated : 3/2/2011
Cassandra L. Kniffin - updated : 1/31/2008
Cassandra L. Kniffin - updated : 1/29/2008

Creation Date:
Victor A. McKusick : 1/25/2008

Edit History:
alopez : 06/07/2024
carol : 04/26/2024
carol : 12/08/2016
carol : 12/08/2016
wwang : 03/03/2011
terry : 3/2/2011
carol : 4/3/2009
carol : 3/4/2008
ckniffin : 1/31/2008
wwang : 1/31/2008
ckniffin : 1/29/2008
ckniffin : 1/29/2008
alopez : 1/25/2008