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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12581
Letter to the Editor
Additional evidence that PGAP1 loss of function causes autosomal recessive global developmental delay and encephalopathy To the Editor: In 2014, a PGAP1 complete loss-of-function genotype was reported in siblings from a consanguineous Syrian family. Both siblings had intellectual disability and encephalopathy (1). The authors suggested that the PGAP1 nullizygous genotype was causal. PGAP1, the gene encoding the post-glycosylphosphatidylinositol (GPI) attachment to proteins 1 protein, is a member of the GPI synthesis pathway (KEGG pathway: ko00563), which already consists of genes causing recessive intellectual disability: PIGA, PIGL, PIGM, PIGV, PIGN, PIGO, PIGQ, PIGT, PIGW, PGAP2 and PGAP3. Consistent with a role in normal development, Pgap1 knock-out mice often result in lethality while mice surviving birth display prominent developmental delay, brain abnormalities, dysmorphisms and growth retardation (1). To securely implicate a new disease gene it is essential to have confirmation from additional families (2). It is also helpful to consider new gene-disease association in light of the patterns of population genetic variation observed in that gene. Here, we provide both the additional clinical and human population genetics support necessary to confirm that complete loss of PGAP1 devastates human development and can cause global developmental delay and encephalopathy. Our patient was referred for evaluation of developmental delay and abnormal brain imaging findings. He was born to non-consanguineous parents at 39 weeks without perinatal complication. After birth, however, he failed to reach developmental milestones. Now, at 3 years, he has significant hypotonia, cortical visual impairment and delays in his gross and fine motor skills. He is functioning at a 6-month-old level with profound delay in language development and relies on a G-tube for nutritional needs (Fig. 1). He displays dyskinetic movements, although, to date, he has never been reported to experience seizures. His initial brain magnetic resonance imaging (MRI) in 2012 revealed mild thinning of the corpus collosum, diminished white matter, prominence of the right posterior Sylvian fissure, and potential cortical dysplasia. Repeated MRI’s in 2012 and 2013 showed diffused volume loss, mild delayed myelination and signal abnormality in the central tegmental tracts of
pons concerning (Fig. 1). There is no evidence of cortical dysplasia. Cortical EEG at 2 years of age showed generalized slowing with no epileptiform changes. Previous chromosomal microarray testing was unremarkable, as was targeted sequencing of DMPK, OCRL, PIP1, NIPBL and FMR1. The child and his parents were enrolled and exome sequenced at Duke University using the HiSeq2500 with KAPA Biosystem’s library followed by whole-exome capture using Nimblegen SeqCap EZV4.0 (Roche NimbleGen, Inc., Madison, WI, USA). This study has been approved by the Institutional Review Board of Duke University. Exome interpretation highlighted a compound heterozygous loss-of-function genotype in PGAP1. PGAP1 is 922 amino-acids long. Our patient inherited a nonsense variant from his heterozygous father NM_024989.3:c.(1572T>A) p.(Tyr524*) that is absent in the Exome Aggregation Consortium (ExAC) database, (3) and inherited a nonsense variant NM_024989.3:c.1396C > T p.(Gln466*) from his heterozygous mother (0.003% allele frequency) (3). Thus, both PGAP1 gene copies had a termination codon mid-protein. PGAP1 is intolerant to functional mutation (http://chgv.org/GenicIntolerance/) (4). More specifically, given the carrier frequency of PGAP1 loss-of-function alleles in a mixed ethnicity population (3), we expect to observe a nullizygous PGAP1 genotype approximately once in every 16.5 million non-consanguineous conceptions (Table S1, Supporting Information). Under an assumption that all PGAP1 nullizygous conceptions survive birth, this estimates to less than 20 PGAP1 nullizygous individuals in the United States. While this bioinformatics signature does not itself implicate PGAP1 nullizygosity with disease, it does provide the confidence required to appropriately interpret a nullizygous PGAP1 genotype as exceptional. Similar to our patient, the earlier reported Syrian siblings presented with hypotonia, developmental delay, encephalopathy and facial dysmorphisms (1) (Table 1). While there is variability in the exact presentation, even between siblings, the broad clinical overlap supports PGAP1 nullizygosity as the genetic cause of their developmental delay and encephalopathy. A homozygous PGAP1 splice variant – classified as a variant of
1
Letter to the Editor
(a)
(b)
(c)
(d)
Fig. 1. The patient is unable to walk, crawl or pull himself up to stand. Significant head lag is noted. He strictly uses a palmer grasp. His language development is profoundly delayed. He has no words and does not attempt to communicate. He has cortical visual impairment. He relies on a G-tube for nutritional needs. He is on the 4th and 27th percentile for height and weight, respectively. He is microcephalic (
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12581
Letter to the Editor
Additional evidence that PGAP1 loss of function causes autosomal recessive global developmental delay and encephalopathy To the Editor: In 2014, a PGAP1 complete loss-of-function genotype was reported in siblings from a consanguineous Syrian family. Both siblings had intellectual disability and encephalopathy (1). The authors suggested that the PGAP1 nullizygous genotype was causal. PGAP1, the gene encoding the post-glycosylphosphatidylinositol (GPI) attachment to proteins 1 protein, is a member of the GPI synthesis pathway (KEGG pathway: ko00563), which already consists of genes causing recessive intellectual disability: PIGA, PIGL, PIGM, PIGV, PIGN, PIGO, PIGQ, PIGT, PIGW, PGAP2 and PGAP3. Consistent with a role in normal development, Pgap1 knock-out mice often result in lethality while mice surviving birth display prominent developmental delay, brain abnormalities, dysmorphisms and growth retardation (1). To securely implicate a new disease gene it is essential to have confirmation from additional families (2). It is also helpful to consider new gene-disease association in light of the patterns of population genetic variation observed in that gene. Here, we provide both the additional clinical and human population genetics support necessary to confirm that complete loss of PGAP1 devastates human development and can cause global developmental delay and encephalopathy. Our patient was referred for evaluation of developmental delay and abnormal brain imaging findings. He was born to non-consanguineous parents at 39 weeks without perinatal complication. After birth, however, he failed to reach developmental milestones. Now, at 3 years, he has significant hypotonia, cortical visual impairment and delays in his gross and fine motor skills. He is functioning at a 6-month-old level with profound delay in language development and relies on a G-tube for nutritional needs (Fig. 1). He displays dyskinetic movements, although, to date, he has never been reported to experience seizures. His initial brain magnetic resonance imaging (MRI) in 2012 revealed mild thinning of the corpus collosum, diminished white matter, prominence of the right posterior Sylvian fissure, and potential cortical dysplasia. Repeated MRI’s in 2012 and 2013 showed diffused volume loss, mild delayed myelination and signal abnormality in the central tegmental tracts of
pons concerning (Fig. 1). There is no evidence of cortical dysplasia. Cortical EEG at 2 years of age showed generalized slowing with no epileptiform changes. Previous chromosomal microarray testing was unremarkable, as was targeted sequencing of DMPK, OCRL, PIP1, NIPBL and FMR1. The child and his parents were enrolled and exome sequenced at Duke University using the HiSeq2500 with KAPA Biosystem’s library followed by whole-exome capture using Nimblegen SeqCap EZV4.0 (Roche NimbleGen, Inc., Madison, WI, USA). This study has been approved by the Institutional Review Board of Duke University. Exome interpretation highlighted a compound heterozygous loss-of-function genotype in PGAP1. PGAP1 is 922 amino-acids long. Our patient inherited a nonsense variant from his heterozygous father NM_024989.3:c.(1572T>A) p.(Tyr524*) that is absent in the Exome Aggregation Consortium (ExAC) database, (3) and inherited a nonsense variant NM_024989.3:c.1396C > T p.(Gln466*) from his heterozygous mother (0.003% allele frequency) (3). Thus, both PGAP1 gene copies had a termination codon mid-protein. PGAP1 is intolerant to functional mutation (http://chgv.org/GenicIntolerance/) (4). More specifically, given the carrier frequency of PGAP1 loss-of-function alleles in a mixed ethnicity population (3), we expect to observe a nullizygous PGAP1 genotype approximately once in every 16.5 million non-consanguineous conceptions (Table S1, Supporting Information). Under an assumption that all PGAP1 nullizygous conceptions survive birth, this estimates to less than 20 PGAP1 nullizygous individuals in the United States. While this bioinformatics signature does not itself implicate PGAP1 nullizygosity with disease, it does provide the confidence required to appropriately interpret a nullizygous PGAP1 genotype as exceptional. Similar to our patient, the earlier reported Syrian siblings presented with hypotonia, developmental delay, encephalopathy and facial dysmorphisms (1) (Table 1). While there is variability in the exact presentation, even between siblings, the broad clinical overlap supports PGAP1 nullizygosity as the genetic cause of their developmental delay and encephalopathy. A homozygous PGAP1 splice variant – classified as a variant of
1
Letter to the Editor
(a)
(b)
(c)
(d)
Fig. 1. The patient is unable to walk, crawl or pull himself up to stand. Significant head lag is noted. He strictly uses a palmer grasp. His language development is profoundly delayed. He has no words and does not attempt to communicate. He has cortical visual impairment. He relies on a G-tube for nutritional needs. He is on the 4th and 27th percentile for height and weight, respectively. He is microcephalic (
