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• Novel biallelic truncating mutation in KLHL7 causing recessive Bohring-Opitz syndrome with central apnea
  Monisha S. Kisling, Carlos R. Ferreira
  Published on: 9 January 2018

• Published on: 9 January 2018

  Novel biallelic truncating mutation in KLHL7 causing recessive Bohring-Opitz syndrome with central apnea

  • Monisha S. Kisling, Genetic Counselor Division of Genetics & Metabolism, Children's National Health System
  • Other Contributors:
    • Carlos R. Ferreira, Medical Geneticist

  We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
  Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
  He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also...

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  We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
  Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
  He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also noted to have a secundum atrial septal defect, and right-sided grade 4 vesicoureteral reflux with reflux nephropathy and hydroureter. An ophthalmology evaluation at age 16 months revealed optic nerve pallor and enlarged optic nerve cups (cup-to-disc ratio 0.6), but no retinal findings. His physical exam is notable for microcephaly (-2 SD), a prominent forehead, low-set ears with uplifted lobes, micrognathia, high palate, bilateral knee and elbow contractures, wrist flexion with ulnar deviation of the wrists and fingers (“BOS posture”), long fingers with camptodactyly and middle finger in palm deformity, prominent heels, a right hydrocele and buried penis, central hypotonia with appendicular hypertonia, and bilateral ankle clonus.
  Whole exome sequencing revealed a novel truncating homozygous mutation in the KLHL7 gene (NM_001031710.2:c.976C>T, p.Arg326*). Parents were each found to carry one copy of the variant.
  We report our patient with many features of patients with KLHL7-related disorder, including IUGR, optic nerve abnormalities, brain abnormalities, central hypotonia, joint contractures,, scoliosis, feeding difficulty and genitourinary and cardiac differences, features overlapping the Crisponi/CISS1-like phenotype and BOS-like phenotype. Our patient was also found to have severe central sleep apnea, well documented by polysomnography. We thus expand the phenotypic and mutational spectrum of KLHL7-related disorders.

  References:
  1 Bruel A-L, Bigoni S, Kennedy J, et al. Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype. J Med Genet 2017;54:830–5.

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  Conflict of Interest:
  None declared.

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