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De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females.

Popp B, Støve SI, Endele S, Myklebust LM, Hoyer J, Sticht H, Azzarello-Burri S, Rauch A, Arnesen T, Reis A - Eur. J. Hum. Genet. (2014)

Bottom Line: A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families.The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used.We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT
Recent studies revealed the power of whole-exome sequencing to identify mutations in sporadic cases with non-syndromic intellectual disability. We now identified de novo missense variants in NAA10 in two unrelated individuals, a boy and a girl, with severe global developmental delay but without any major dysmorphism by trio whole-exome sequencing. Both de novo variants were predicted to be deleterious, and we excluded other variants in this gene. This X-linked gene encodes N-alpha-acetyltransferase 10, the catalytic subunit of the NatA complex involved in multiple cellular processes. A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families. This rare disorder is characterized by a highly recognizable phenotype, global developmental delay and results in death during infancy. In an attempt to explain the discrepant phenotype, we used in vitro N-terminal acetylation assays which suggested that the severity of the phenotype correlates with the remaining catalytic activity. The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used. We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.

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(a) Individual II-3 of family A at age 2 years and 11 months. (b) Individual II-1 of family B at age 5 years and 11 months; only minor dysmorphisms and no syndromic features were observed.
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fig2: (a) Individual II-3 of family A at age 2 years and 11 months. (b) Individual II-1 of family B at age 5 years and 11 months; only minor dysmorphisms and no syndromic features were observed.

Mentions: Previously, we described a probable disease-causing hemizygous de novo missense variant c.346C>T p.(Arg116Trp) in NAA10 in a boy (individual II-1 from family B) with severe developmental delay.24 Using exome sequencing, we now identified a further heterozygous de novo variant c.319G>T p.(Val107Phe) in a girl (individual II-3 from family A) presenting with severe global developmental delay (Figures 1a–c). Both individuals described here show severe global developmental delay, growth retardation and some overlapping features as summarized in Table 1 (see also Figure 2).


De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females.

Popp B, Støve SI, Endele S, Myklebust LM, Hoyer J, Sticht H, Azzarello-Burri S, Rauch A, Arnesen T, Reis A - Eur. J. Hum. Genet. (2014)

(a) Individual II-3 of family A at age 2 years and 11 months. (b) Individual II-1 of family B at age 5 years and 11 months; only minor dysmorphisms and no syndromic features were observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402627&req=5

fig2: (a) Individual II-3 of family A at age 2 years and 11 months. (b) Individual II-1 of family B at age 5 years and 11 months; only minor dysmorphisms and no syndromic features were observed.
Mentions: Previously, we described a probable disease-causing hemizygous de novo missense variant c.346C>T p.(Arg116Trp) in NAA10 in a boy (individual II-1 from family B) with severe developmental delay.24 Using exome sequencing, we now identified a further heterozygous de novo variant c.319G>T p.(Val107Phe) in a girl (individual II-3 from family A) presenting with severe global developmental delay (Figures 1a–c). Both individuals described here show severe global developmental delay, growth retardation and some overlapping features as summarized in Table 1 (see also Figure 2).

Bottom Line: A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families.The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used.We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT
Recent studies revealed the power of whole-exome sequencing to identify mutations in sporadic cases with non-syndromic intellectual disability. We now identified de novo missense variants in NAA10 in two unrelated individuals, a boy and a girl, with severe global developmental delay but without any major dysmorphism by trio whole-exome sequencing. Both de novo variants were predicted to be deleterious, and we excluded other variants in this gene. This X-linked gene encodes N-alpha-acetyltransferase 10, the catalytic subunit of the NatA complex involved in multiple cellular processes. A single hypomorphic missense variant p.(Ser37Pro) was previously associated with Ogden syndrome in eight affected males from two different families. This rare disorder is characterized by a highly recognizable phenotype, global developmental delay and results in death during infancy. In an attempt to explain the discrepant phenotype, we used in vitro N-terminal acetylation assays which suggested that the severity of the phenotype correlates with the remaining catalytic activity. The variant in the Ogden syndrome patients exhibited a lower activity than the one seen in the boy with intellectual disability, while the variant in the girl was the most severe exhibiting only residual activity in the acetylation assays used. We propose that N-terminal acetyltransferase deficiency is clinically heterogeneous with the overall catalytic activity determining the phenotypic severity.

Show MeSH
Related in: MedlinePlus