Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy

Leah Fleming, Monica Lemmon, Natalie Beck, Maria Johnson, Weiyi Mu, David Murdock, Joann N Bodurtha, Julie E Hoover Fong, Ronald Cohn, Thangamadhan Bosemani, Kristin Baranano, Ada Hamosh

Research output: Contribution to journalArticle

Abstract

Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume170
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Muscle Hypotonia
Genetic Association Studies
Epilepsy
Seizures
Finger Phalanges
Micrognathism
Mutation
Hypertelorism
Exome
Generalized Epilepsy
Glycosylphosphatidylinositols
Quadriplegia
Muscle Spasticity
Palate
Toes
Eyelids
Gastroesophageal Reflux
Lip
Nails
Nose

Keywords

  • Congenital disorders of glycosylation
  • Epilepsy
  • Genotype-phenotype association
  • Glycosylphosphatidylinositol anchors
  • GPI ethanolamine phosphate transferase 1
  • Human
  • Hypotonia
  • Infantile
  • Intractable
  • PIGN
  • Spasms

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. / Fleming, Leah; Lemmon, Monica; Beck, Natalie; Johnson, Maria; Mu, Weiyi; Murdock, David; Bodurtha, Joann N; Hoover Fong, Julie E; Cohn, Ronald; Bosemani, Thangamadhan; Baranano, Kristin; Hamosh, Ada.

In: American Journal of Medical Genetics, Part A, Vol. 170, No. 1, 01.01.2016, p. 77-86.

Research output: Contribution to journalArticle

Fleming, Leah ; Lemmon, Monica ; Beck, Natalie ; Johnson, Maria ; Mu, Weiyi ; Murdock, David ; Bodurtha, Joann N ; Hoover Fong, Julie E ; Cohn, Ronald ; Bosemani, Thangamadhan ; Baranano, Kristin ; Hamosh, Ada. / Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. In: American Journal of Medical Genetics, Part A. 2016 ; Vol. 170, No. 1. pp. 77-86.
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AU - Murdock, David

AU - Bodurtha, Joann N

AU - Hoover Fong, Julie E

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