#618548
Table of Contents
Alternative titles; symbols
Location | Phenotype | Inheritance |
Phenotype mapping key |
Phenotype MIM number |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
16p13.3 | Multiple congenital anomalies-hypotonia-seizures syndrome 4 | AR | 3 | 618548 | PIGQ | 605754 |
18q21.33 | Multiple congenital anomalies-hypotonia-seizures syndrome 1 | AR | 3 | 614080 | PIGN | 606097 |
20q13.12 | Multiple congenital anomalies-hypotonia-seizures syndrome 3 | AR | 3 | 615398 | PIGT | 610272 |
Xp22.2 | Multiple congenital anomalies-hypotonia-seizures syndrome 2 | XLR | 3 | 300868 | PIGA | 311770 |
A number sign (#) is used with this entry because of evidence that multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is caused by homozygous or compound heterozygous mutation in the PIGQ gene (605754) on chromosome 16p13.
Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months of life. Patients have severe global developmental delay, and may have additional variable features, including dysmorphic or coarse facial features, visual defects, and mild skeletal or renal anomalies. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Starr et al., 2019).
For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080).
For a discussion of genetic heterogeneity of DEE, see 308350.
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Martin et al. (2014) reported a child of West African descent (patient 4) with onset of refractory seizures at age 4 weeks and profoundly delayed psychomotor development. Brain imaging showed delayed and reduced myelination; he died of a respiratory infection at age 2 years, 4 months. Clinical details were limited.
Alazami et al. (2015) reported a patient, born of consanguineous parents, with intractable seizures, developmental delay, and optic atrophy. Clinical details were limited.
Starr et al. (2019) reported a boy, born of unrelated parents, with a complex multisystem disorder resulting in death at 10 months of age. The pregnancy was complicated by severe polyhydramnios, but there were no significant neonatal issues. He presented around 4 months of age with hypotonia, poor head control, poor feeding, and gasping episodes. He had coarse dysmorphic facial features, including hooded upper eyelids, mild ptosis, telecanthus, fleshy and uplifted ear lobes, thick alae nasi with broad nasal tip, anteverted nares, full cheeks, long and smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth, and mild micrognathia. He also had pectus excavatum, diastasis recti, inguinal hernia, abdominal wall laxity, soft and sagging skin, and deep plantar creases. Ophthalmic involvement included vertical nystagmus, hyperopia, astigmatism, cortical visual impairment, and alacrima. The kidneys showed multiple small renal cortical cysts, and he had vesicoureteral reflux, but kidney function was normal. The boy developed refractory myoclonic and multifocal seizures around 7 months of age; EEG showed high amplitude spike and slow wave complexes. Imaging studies showed plagiocephaly, ventriculomegaly, large anterior fontanel, sphenoid wing dysplasia, scoliosis, and transient lesions in the long bones. Alkaline phosphatase levels were persistently elevated. At age 10 months, he developed a febrile infection that resulted in seizures and death.
Johnstone et al. (2020) reported 7 patients from 6 families with PIGQ mutations. Four of the patients had died, 1 at 2 days of life secondary to cardiac and renal failure and 3 between 9 months and 5 years of age. Neonatal complications included respiratory distress in 4 patients and jaundice in 2. In the 6 patients who survived the neonatal period, seizure onset occurred between 2.5 and 7 months of age, and all 6 had severe to profound global developmental delay and visual problems. Six of 7 patients had facial dysmorphisms, including coarse facies and macroglossia. Three patients had pectus excavatum, 1 had inverted nipples, 1 had scoliosis, and 3 had delayed dentition. Cardiac anomalies were seen in 6 patients, including 3 with heart block and arrhythmia, 1 with pulmonary hypertension, and 1 with pulmonary stenosis. In 4 of 6 patients with available study imaging, brain MRI showed poor or incomplete myelination or demyelination. Additional MRI findings included pituitary hypoplasia in 1 patient, volume loss of the vermis in 1, and dangling choroids in 1.
The transmission pattern of MCAHS4 in the family reported by Starr et al. (2019) was consistent with autosomal recessive inheritance.
In a child of West African descent with MCAHS4, Martin et al. (2014) identified a homozygous splice site mutation in the PIGQ gene (605754.0001). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation occurred before the catalytic domain of PIGQ, suggesting that it abrogated the function of the enzyme and led to a reduction in GPI synthesis. Transfection of the mutation into PIGQ-deficient CHO cells did not restore GPI-anchored protein expression as efficiently as wildtype, and expression of the mutant protein was decreased compared to wildtype, consistent with a loss-of-function effect.
In a patient (12DG0223) with MCAHS4, Alazami et al. (2015) identified a homozygous nonsense mutation in the PIGQ gene (R207X; 605754.0002). The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the PIGQ variant and studies of patient cells were not performed.
In a male infant with MCAHS4, Starr et al. (2019) identified compound heterozygous mutations in the PIGQ gene (605765.0003 and 605754.0004). The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent, confirming segregation within the family. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to have a loss-of-function effect.
In 7 patients from 6 families with MCAHS4, Johnstone et al. (2020) identified 8 different mutations in the PIGQ gene (see, e.g., 605754.0004-605754.0006), 7 of which were novel, in homozygous or compound heterozygous state. The mutations were identified by whole-exome sequencing.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065, related citations] [Full Text]
Johnstone, D. L., Nguyen, T. T. M., Zambonin, J., Kernohan, K. D., St-Denis, A., Baratang, N. V., Hartley, T., Geraghty, M. T., Richer, J., Majewski, J., Bareke, E., Guerin, A., and 12 others. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: report of seven new subjects and review of the literature. J. Inherit. Metab. Dis. 43: 1321-1332, 2020. Note: Erratum: J. Inherit. Metab. Dis. 46: 156 only, 2023. [PubMed: 32588908, images, related citations] [Full Text]
Martin, H. C., Kim, G. E., Pagnamenta, A. T., Murakami, Y., Carvill, G. L., Meyer, E., Copley, R. R., Rimmer, A., Barcia, G., Fleming, M. R., Kronengold, J., Brown, M. R., and 21 others. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum. Molec. Genet. 23: 3200-3211, 2014. [PubMed: 24463883, images, related citations] [Full Text]
Starr, L. J., Spranger, J. W., Rao, V. K., Lutz, R., Yetman, A. T. PIGQ glycosylphosphatidylinositol-anchored protein deficiency: characterizing the phenotype. Am. J. Med. Genet. 179A: 1270-1275, 2019. [PubMed: 31148362, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 1934; DO: 0112213;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
16p13.3 | Multiple congenital anomalies-hypotonia-seizures syndrome 4 | 618548 | Autosomal recessive | 3 | PIGQ | 605754 |
A number sign (#) is used with this entry because of evidence that multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is caused by homozygous or compound heterozygous mutation in the PIGQ gene (605754) on chromosome 16p13.
Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months of life. Patients have severe global developmental delay, and may have additional variable features, including dysmorphic or coarse facial features, visual defects, and mild skeletal or renal anomalies. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Starr et al., 2019).
For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080).
For a discussion of genetic heterogeneity of DEE, see 308350.
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Martin et al. (2014) reported a child of West African descent (patient 4) with onset of refractory seizures at age 4 weeks and profoundly delayed psychomotor development. Brain imaging showed delayed and reduced myelination; he died of a respiratory infection at age 2 years, 4 months. Clinical details were limited.
Alazami et al. (2015) reported a patient, born of consanguineous parents, with intractable seizures, developmental delay, and optic atrophy. Clinical details were limited.
Starr et al. (2019) reported a boy, born of unrelated parents, with a complex multisystem disorder resulting in death at 10 months of age. The pregnancy was complicated by severe polyhydramnios, but there were no significant neonatal issues. He presented around 4 months of age with hypotonia, poor head control, poor feeding, and gasping episodes. He had coarse dysmorphic facial features, including hooded upper eyelids, mild ptosis, telecanthus, fleshy and uplifted ear lobes, thick alae nasi with broad nasal tip, anteverted nares, full cheeks, long and smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth, and mild micrognathia. He also had pectus excavatum, diastasis recti, inguinal hernia, abdominal wall laxity, soft and sagging skin, and deep plantar creases. Ophthalmic involvement included vertical nystagmus, hyperopia, astigmatism, cortical visual impairment, and alacrima. The kidneys showed multiple small renal cortical cysts, and he had vesicoureteral reflux, but kidney function was normal. The boy developed refractory myoclonic and multifocal seizures around 7 months of age; EEG showed high amplitude spike and slow wave complexes. Imaging studies showed plagiocephaly, ventriculomegaly, large anterior fontanel, sphenoid wing dysplasia, scoliosis, and transient lesions in the long bones. Alkaline phosphatase levels were persistently elevated. At age 10 months, he developed a febrile infection that resulted in seizures and death.
Johnstone et al. (2020) reported 7 patients from 6 families with PIGQ mutations. Four of the patients had died, 1 at 2 days of life secondary to cardiac and renal failure and 3 between 9 months and 5 years of age. Neonatal complications included respiratory distress in 4 patients and jaundice in 2. In the 6 patients who survived the neonatal period, seizure onset occurred between 2.5 and 7 months of age, and all 6 had severe to profound global developmental delay and visual problems. Six of 7 patients had facial dysmorphisms, including coarse facies and macroglossia. Three patients had pectus excavatum, 1 had inverted nipples, 1 had scoliosis, and 3 had delayed dentition. Cardiac anomalies were seen in 6 patients, including 3 with heart block and arrhythmia, 1 with pulmonary hypertension, and 1 with pulmonary stenosis. In 4 of 6 patients with available study imaging, brain MRI showed poor or incomplete myelination or demyelination. Additional MRI findings included pituitary hypoplasia in 1 patient, volume loss of the vermis in 1, and dangling choroids in 1.
The transmission pattern of MCAHS4 in the family reported by Starr et al. (2019) was consistent with autosomal recessive inheritance.
In a child of West African descent with MCAHS4, Martin et al. (2014) identified a homozygous splice site mutation in the PIGQ gene (605754.0001). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation occurred before the catalytic domain of PIGQ, suggesting that it abrogated the function of the enzyme and led to a reduction in GPI synthesis. Transfection of the mutation into PIGQ-deficient CHO cells did not restore GPI-anchored protein expression as efficiently as wildtype, and expression of the mutant protein was decreased compared to wildtype, consistent with a loss-of-function effect.
In a patient (12DG0223) with MCAHS4, Alazami et al. (2015) identified a homozygous nonsense mutation in the PIGQ gene (R207X; 605754.0002). The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the PIGQ variant and studies of patient cells were not performed.
In a male infant with MCAHS4, Starr et al. (2019) identified compound heterozygous mutations in the PIGQ gene (605765.0003 and 605754.0004). The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent, confirming segregation within the family. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to have a loss-of-function effect.
In 7 patients from 6 families with MCAHS4, Johnstone et al. (2020) identified 8 different mutations in the PIGQ gene (see, e.g., 605754.0004-605754.0006), 7 of which were novel, in homozygous or compound heterozygous state. The mutations were identified by whole-exome sequencing.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065] [Full Text: https://doi.org/10.1016/j.celrep.2014.12.015]
Johnstone, D. L., Nguyen, T. T. M., Zambonin, J., Kernohan, K. D., St-Denis, A., Baratang, N. V., Hartley, T., Geraghty, M. T., Richer, J., Majewski, J., Bareke, E., Guerin, A., and 12 others. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: report of seven new subjects and review of the literature. J. Inherit. Metab. Dis. 43: 1321-1332, 2020. Note: Erratum: J. Inherit. Metab. Dis. 46: 156 only, 2023. [PubMed: 32588908] [Full Text: https://doi.org/10.1002/jimd.12278]
Martin, H. C., Kim, G. E., Pagnamenta, A. T., Murakami, Y., Carvill, G. L., Meyer, E., Copley, R. R., Rimmer, A., Barcia, G., Fleming, M. R., Kronengold, J., Brown, M. R., and 21 others. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum. Molec. Genet. 23: 3200-3211, 2014. [PubMed: 24463883] [Full Text: https://doi.org/10.1093/hmg/ddu030]
Starr, L. J., Spranger, J. W., Rao, V. K., Lutz, R., Yetman, A. T. PIGQ glycosylphosphatidylinositol-anchored protein deficiency: characterizing the phenotype. Am. J. Med. Genet. 179A: 1270-1275, 2019. [PubMed: 31148362] [Full Text: https://doi.org/10.1002/ajmg.a.61185]
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