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Participant 196

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Male, passed away at 19 months, with poor growth, small head (severe progressive microcephaly), global developmental delay, vision and hearing impairment, autoimmune disease, and brain abnormalities thought to be caused by a complex duplication involving the genes ATAD3B and ATAD3A and ATAD3C.

Date of Report

Mar 16, 2022


The participant was born full-term after a pregnancy that was normal except for well-controlled gestational diabetes. His head was smaller than expected (fetal microcephaly) beginning at 30 weeks gestation. At birth, he was noted to be small in size and have corneal clouding, small corneas (microcornea), small eyes (microphthalmia), and a small penis (micropenis). His eye findings normalized over time but he continued to have visual impairment due to nearsightedness (high myopia) and damage in the brain (cerebral visual impairment). The newborn screening hearing test was abnormal and follow-up testing confirmed hearing loss (sensorineural hearing loss).

At about 3 months, the participant was diagnosed with Graves’ disease (autoimmune hyperthyroidism) and had his thyroid removed at 9 months. Liver function tests showed elevated enzyme levels that were suspicious for liver damage or inflammation. Follow-up tests did not provide a more specific diagnosis. The participant also had difficulties feeding that required a G-tube.

The participant was found to have global developmental delay, muscle weakness closer to the torso (proximal weakness), low muscle tone (hypotonia), and increased muscle tone (hypertonia) at different areas in the body. He did not have seizures, but an EEG was abnormal, indicating disease in the brain (mild generalized encephalopathy). Brain MRIs did confirm multiple structural brain abnormalities and calcium buildup (calcifications).

The participant was diagnosed with heart disease (left ventricular hypertrophy), mild enlargement of the aorta (aortic dilation), and backward flow of blood through some valves in the heart (moderate aortic, mitral, and bicuspid valve regurgitation). His left ventricular hypertrophy and valvular regurgitation improved after his thyroidectomy but did not go away.

At approximately 15 months, the participant began experiencing episodes in which his breathing stopped (central apnea) and his heart rate slowed (bradycardia). These episodes worsened over time, and the participant passed away at 19 months. An autopsy confirmed the findings that were seen in life and noted some additional findings, including a rare cardiac disorder (histiocytoid cardiomyopathy), abnormal blood vessels between the heart and lungs (pulmonary vasculature), and inflammation of the brain (encephalitis).

Exome sequencing revealed that part of the participant’s DNA was duplicated in an area that included the genes ATAD3A, ATAD3B, and ATAD3C. It is now believed that this genetic change was the cause of his condition.

Symptoms / Signs
  • Brain abnormalities (progressive cerebral atrophy and thinning of the corpus callosum, delayed myelination, symmetric linear calcification involving the periventricular regions, corpus callosum, and cerebellum, small and dysmorphic pons, focal microgyria, encephalitis of the brainstem and cerebral cortex, multiple findings suggestive of mitochondrial dysfunction seen on autopsy)
  • Growth abnormalities (very short stature and head size that began prior to birth)
  • Severe global developmental delay
  • Decreased muscle tone in the torso (axial hypotonia)
  • Muscle weakness in the limbs near the torso (proximal muscle weakness)
  • Increased muscle tone in upper and lower extremities (hypertonia)
  • Eye abnormalities (cerebral visual impairment, high myopia, exotropia)
  • Hearing loss (bilateral sensorineural hearing loss)
  • Facial differences (micro-retrognathia, full cheeks, up-slanted palpebral fissures)
  • Heart abnormalities (left ventricular hypertrophy, histiocytoid cardiomyopathy seen on autopsy, mild dilation of the ascending aorta, congenital abnormalities of the pulmonary vasculature)
  • Gastrointestinal abnormalities (difficulty swallowing (dysphagia), gastroesophageal reflux, elevated liver function tests (transaminitis), inflammation of the liver (non-specific hepatitis))
  • Skeletal abnormalities (boutonniere-like deformity of 5th fingers, short great toes with medial angulation, premature fusion of the skull bones (acquired craniosynostosis))
  • Abnormalities of the skin and teeth (eczema, linear skin defects, lack of eruption of baby teeth)
  • Small penis (micropenis)
  • Graves’ disease (autoimmune thyroid disease)
Current Treatments
Prior Treatments
  • Gastrostomy tube (G-tube) insertion
  • Omeprazole
  • Potassium iodide
  • Thyroidectomy
Considered treatments
Previously Considered Diagnoses
  • Chondrodysplasia punctata and related disorders
  • Chromosomal aneuploidy and structural abnormalities
  • Copy number variant disorders
  • Metabolic disorders (including peroxisomal fatty acid oxidation disorders)
Other Photographs
Genetic Variants of Interest

Clinicians and researchers have identified the following de novo duplication, involving all of ATAD3B and part of ATAD3A and ATAD3C, to be causing the participant’s symptoms.  The variant is thought to be the result of a complex chromosomal rearrangement, and further investigation is underway. 

Inheritance Pattern
Position (hg19)
DNA Change
Protein Change
chr1:g.1404883_ 1451417dup
~47kb complex duplication involving ATAD3A/B/C
chr1:g.1404883_ 1451417dup
~47kb complex duplication involving ATAD3A/B/C
chr1:g.1404883_ 1451417dup
~47kb complex duplication involving ATAD3A/B/C

If this participant sounds like you or someone you know, please contact us!


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