A novel de novo microdeletion at 17q11.2 adjacent to NF1 gene associated with developmental delay, short stature, microcephaly and dysmorphic features
Here we presented a 17q11.2 de novo deletion characterized by SNP array in a patient with developmental delay and mild dysmorphic features. This is a novel deletion, relative large in size and not listed among the reported CNVs in phenotypically normal individuals in the Database of Genomic Variants, therefore, it is considered as a likely pathogenic CNV.
We searched literature and databases for overlapping deletions at this interval without the involvement of NF1 gene. There are only four deletion cases currently reported within this interval, all are much smaller in size (Fig. 2b). One (nsv1062993) is reported in the morbidity map of developmental delay, and the other three (#250045, #287702, #1973) are reported in the Decipher database. The case #250045, presented with microcephaly and seizures, carrying a de novo deletion of 38 kb (chr17:27771342-27809321) involving part of TAOK1 gene. The case with 72 kb deletion (chr17:27730573-27802767) from the morbidity map of developmental delay (nsv1062993) also intercept with TAOK1 gene but the inheritance status and detailed clinical phenotypes are not known, except the patient is presumed to have developmental delay. The deletion nsv1062993 completely overlaps the CNV of #250045, and the two partial overlap TAOK1 gene, we assume that TAOK1 gene plays an important role in the phenotype of patient. The patient #287702 carried a de novo deletion of 17q11.2 (chr17:27837697-28120076) and a maternally inherited duplication of 15q13.3, and showed dysphasia, poor motor coordination and specific learning disability. The patient #1973 carried a deletion of 173 kb (chr17:28496019-28669139) in size, involving genes including SLC6A4, BLMH and part of NSRP1. He showed depression, intellectual disability and psychosis. The breakpoints of this four cases are different, however, their phenotype have some common ground, mainly defined on the basis of the central nervous system.
There are a total of 43 RefSeq genes involved in the deletion in our patient. Seven genes (FAM222B, BLMH, PHF12, CRYBA1, NUFIP2, TAOK1 and SLC6A4) were predicted to have a haploinsufficiency score less than 10, suggestive of possible clinical consequences with one copy deletion. Little clue is available about the potential relationship of FAM222B and BLMH with neurodevelopment. PHF12 is a type of PHD (plant homeodomain) finger protein, acts as a transcriptional repressor. Several proteins with PHD finger are known to epigenetically regulate gene expression and loss of function mutations are associated with intellectual disability phenotypes in human [7, 8]. CRYBA1 is one of the ?-crystallins families, encoding both the beta-A3- and beta-A1-crystallins. Different beta-crystallin proteins can interact with each other and other lens proteins, which play a key role in maintaining the transparency of the lens. The mutations of CRYBA1 may be destroy the structure and function of crystallins leading to abnormalities in the development and maturation of the retinal vasculature, and have been identified to be causative for congenital cataracts [9, 10]. Up to now, the patient did not present typical phenotype of congenital cataracts, it may be associated with the phenotypic heterogeneity of congenital cataracts.
NUFIP2 (nuclear fragile X mental retardation protein interacting protein 2) gene encodes an 82-kD protein (called 82-FIP), distributed in various regions of the brain. It was demonstrated that NUFIP2 interacts with FMRP, whose absence causes the fragile-X syndrome [11]. 82-FIP might have a role in the development of the nervous system and in cognitive function. The deregulation of NUFIP2 was reported to be associated with mental retardation or cognitive impairment [12].
The gene of TAOK1 has the lowest predicted haploinsufficiency score. It encodes hTAOK1, which is a member of the Ste20 group of kinases with the kinase domain located at the N-terminus. hTAOK1 was initially cloned from human fetal brain [13], and highly expressed in human brain, as shown by Northern analysis (http://www.kazusa.or.jp/huge/gfpage/KIAA1361/). TAOK1 may play a role in the developing human brain by inducing neuronal apoptosis and regulating microtubule dynamics and checkpoint signaling [14, 15]. Of significance, the case nsv1062993 and #250045 both partially overlapped TAOK1 gene, presenting developmental delay and microcephaly, respectively. Accordingly, we hypothesize that TAOK1 might be involved in the developmental delay and microcephaly in our patient. In addition, a closely related family member TAOK2 is regarded as a autism spectrum disorder susceptibility gene, are shown to regulated basal dendrite development in cortical neurons [16].
The solute carrier family 6 (serotonin neurotransmitter transporter) member 4 gene (SLC6A4) encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. Therefore, SLC6A4 gene may play a role in terminating the synaptic actions of serotonin and recycles it into the neurotransmitter pool [17]. Allelic heterogeneity at this gene have been implicated in speech delay, atypical autism, anxiety and obsessive compulsive disorder [18].
In addition, several other genes are known to be functionally important for the development and function of the central nervous system.
SEZ6 (seizure related 6 homolog (mouse)) specific expresses in the brain, especially in the developing forebrain [19]. SEZ6 may have the function on cell adhesion or recognition and protein-protein interaction [20]. The mutations of SEZ6 were associated with febrile seizures and epilepsy [21].
GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) is a multifunctional signaling adaptor protein. GIT1 interacts with various proteins and forms signaling complex to modulate the development of dendritic spines and neuronal synapses [22]. Git1–/– mice and dGitex21C Drosophila mutant were studied and displayed a microcephaly-like brain size reduction decreased neuronal cell body size, and behavioral deficits such as impaired motor coordination and learning [23].
TRAF4 gene encodes a member of the TNF receptor associated factor (TRAF) family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. TRAF4 protein has been shown to interact with neurotrophin receptor, p75 (NTR/NTSR1), and negatively regulate NTR induced cell death and NF-kappa B activation [24]. TRAF4-deficient mice exhibited a high incidence of spina bifida, a defect likened to neural tube defects (NTDs), which revealed that TRAF4 participates in neurulation in vivo [25].
Thus, multiple genes at this interval are likely contributing to the clinical presentations of our patient. Further study is warranted to understand the underlying pathological mechanism.