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Condition report · Neurological

Au-Kline Syndrome (HNRNPK)

Whole genome sequencing reads the HNRNPK gene for the changes that cause Au-Kline syndrome, a developmental condition with intellectual disability, low muscle tone and distinctive facial features.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A rare developmental syndrome causing intellectual disability, low muscle tone and distinctive facial features, often with heart, kidney or skeletal differences. It results from loss of one working copy of the HNRNPK gene.

Au-Kline syndrome is a rare developmental condition that causes intellectual disability and low muscle tone. Typical facial features include long eye openings, droopy eyelids, a broad nose and a downturned mouth. Speech and walking are often delayed, and some children are never able to speak or walk independently.

It results from loss of one working copy of HNRNPK, a protein that binds DNA and RNA and helps control the activity of many genes. Congenital heart defects and hydronephrosis, a swelling of the kidney caused by urine backing up, are reported in most affected people. Skeletal differences, feeding difficulties and hearing loss also occur, and some people have autonomic changes such as a high pain threshold and heat intolerance.

Most cases arise new, but each child of an affected person has a 50% chance of inheriting the change, so genetic counselling and parental testing guide recurrence risk. Management includes heart, skeletal, kidney, hearing and eye checks, along with developmental, educational and therapy support.

The condition we analyse

Autosomal dominant

Au-Kline syndrome is caused by a change in one copy of HNRNPK, an RNA-binding protein that controls the activity of many genes, usually through variants that stop it working. Most cases arise de novo.

Signs and symptoms

Developmental delay and intellectual disability, low muscle tone and distinctive facial features such as long eye openings, droopy eyelids and a broad nose are typical. Congenital heart defects and kidney differences such as hydronephrosis are common, and skeletal differences also occur. Less often there are feeding difficulties, hearing loss, cleft palate or craniosynostosis.

What a diagnosis changes

Management includes heart, skeletal, kidney, hearing and eye assessment, with developmental, educational and therapy support. Most cases arise de novo, but each child of an affected person has a 50% chance of inheriting the change, so genetic counselling and parental testing guide recurrence risk.

Genes analysed

Includes 2 related subtypes ↓
  • Au-Kline syndrome
  • neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome due to 9q21 microdeletion
MONDO:0018681Orphanet 453499Sources: [1][2][3]

Why whole genome sequencing

Au-Kline syndrome usually arises new, but each child of an affected person still has a 1 in 2 chance of inheriting the change.

Several organs need checking

Heart, kidney, skeletal and eye checks are part of routine care, because differences in these systems are common. Anaesthesia advice is suggested before any sedation, as a large tongue and bite problems can cause airway issues.

Missense changes widen the picture

A 2022 study of 32 people found that some missense changes cause subtle facial features with few or no malformations, widening the known range. Clinical criteria have been proposed to tell Au-Kline syndrome apart from the similar Kabuki syndrome.

References

  1. Au PYB, McNiven V, Phillips L, Innes AM, Kline AD, 2019. Au-Kline Syndrome. GeneReviews
  2. Au-Kline syndrome. MedlinePlus Genetics
  3. Choufani S, McNiven V, Cytrynbaum C, Jangjoo M, Adam MP, Bjornsson HT et al., 2022. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. American journal of human genetics

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