TY - JOUR
T1 - Expanding the spectrum of phenotypes associated with germline PIGA mutations
T2 - a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities
AU - van der Crabben, Saskia N
AU - Harakalova, Magdalena
AU - Brilstra, Eva H
AU - van Berkestijn, Frédérique M C
AU - Hofstede, Floris C
AU - van Vught, Adrianus J
AU - Cuppen, Edwin
AU - Kloosterman, Wigard
AU - Ploos van Amstel, Hans Kristian
AU - van Haaften, Gijs
AU - van Haelst, Mieke M
N1 - © 2013 Wiley Periodicals, Inc.
PY - 2014/1
Y1 - 2014/1
N2 - Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.
AB - Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.
KW - Abnormalities, Multiple/diagnosis
KW - Alkaline Phosphatase/blood
KW - Brain/pathology
KW - Chromosome Segregation
KW - Chromosomes, Human, X
KW - Developmental Disabilities/diagnosis
KW - Exome
KW - Germ-Line Mutation
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - Infant
KW - Magnetic Resonance Imaging
KW - Male
KW - Membrane Proteins/genetics
KW - Pedigree
KW - Phenotype
KW - X Chromosome Inactivation
U2 - https://doi.org/10.1002/ajmg.a.36184
DO - https://doi.org/10.1002/ajmg.a.36184
M3 - Review article
C2 - 24259184
SN - 1552-4825
VL - 164A
SP - 29
EP - 35
JO - American Journal of Medical Genetics Part A
JF - American Journal of Medical Genetics Part A
IS - 1
ER -