Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.
Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.
Ruqaiah
R
Altassan
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Haya Al
HA
Saud
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Tariq Ahmad
TA
Masoodi
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Haya Al
HA
Dosssari
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.|Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Ola
O
Khalifa
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.|College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
Hamad
H
Al-Zaidan
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.
Nadia
N
Sakati
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.
Zuhair
Z
Rhabeeni
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.|College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
Zuhair
Z
Al-Hassnan
College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.|Department of Dermatology, King Faisal Specialist.
Yousef
Y
Binamer
Department of Pediatrics, Royal hospital, Muscat, Oman.
Nadia
N
Alhashemi
Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
William
W
Wade
Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Zayed
Z
Al-Zayed
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.
Moeen
M
Al-Sayed
Department of Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Mohamed A
MA
Al-Muhaizea
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Brian
B
Meyer
Department of Medical Genetics, King Faisal Specialist Hospital and Center Hospital, Riyadh, Saudi Arabia.|College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
Mohammad
M
Al-Owain
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Salma M
SM
Wakil
D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1; D018389:Codon, Nonsense; D003241:Consanguinity; D059472:Exome; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007007:Hypohidrosis / Q000503:physiopathology; D008607:Intellectual Disability / Q000503:physiopathology; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding; D017433:Protein Structure, Secondary; D020917:Receptor, trkA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012529:Saudi Arabia; D016728:Self-Injurious Behavior / Q000503:physiopathology; D012720:Severity of Illness Index
D018389:Codon, Nonsense; C502240:NGF protein, human; D020932:Nerve Growth Factor; D020917:Receptor, trkA
ADHD-attention deficit hyperactivity disorder; CIPA-congenital insensitivity to pain with anhidrosis; HSAN-hereditary sensory and autonomic neuropathy; NGF-nerve growth factor; NTRK1-neurotrophic tyrosine kinase receptor type 1