A novel description of a syndrome consisting of 7q21.3 deletion including DYNC1I1 with preserved DLX5/6 without ectrodactyly: a case report

We report the case of a 44-year-old mestizo (combined European and Amerindian descent) man born to non-consanguineous parents. He is the first of two children conceived by a 25-year-old mother and a 34-year-old father; he has no relevant prenatal history and no known family history of congenital malformations, although his father was diagnosed with schizophrenia. There was no known exposure to teratogenic drugs, infections, or radiation. He was born at 41-week gestation by normal vaginal delivery.

He underwent multiple reconstructive surgeries 15 years prior to our evaluation, where mandibular hypoplasia and prominent low-set ears were corrected. Photographs from childhood showed epicanthal fold, fullness of upper eyelid, depressed nasal bridge, anteverted nares, long philtrum, malocclusion, micrognathia, retrognathia, full cheeks, and prominent low-set ears.

His first physical evaluation at our institution was performed at age 42. Clinical findings included male pattern baldness and black hair with multiple strands of gray hair, stenosis of the cartilaginous portion of his external auditory canal and low-set ears, long uvula, enlarged thyroid gland, mitral murmur, kyphoscoliosis, bilateral inguinal herniae, erythematous and scaly lesions of his feet consistent with tinea pedis, as well as discolored yellow-green nails consistent with onychomycosis.

Echocardiography revealed impaired relaxation grade 1 and mild prolapse of the anterior leaflet of his mitral valve. Audiometry reported bilateral sensorineural hearing loss; the test was limited by the presence of cerumen impaction mainly in his right auditory canal. Computed tomography revealed surgical evidence in inferior maxillary bone, showing signs of microgenia, retrognathia, and a slight abnormality of dental occlusion. His infratentorial and supratentorial brain parenchyma was of normal density. Wormian bones were identified in his occipital cranial region (Fig. 1). The shape of his skull had a mild dolichocephalic configuration. His right ear presented cerumen impaction of 16.0×10.5 mm. His middle and inner ear structures were without abnormalities.

A Minnesota Multiphasic Personality Inventory-2 (MMPI-2) [4] showed an elevated psychological profile on the scales of hysteria, hypochondriasis, and paranoia; the patient appeared to be socially balanced, extraverted, and open to new experiences, as well as spontaneous, controlling, excessively rational, rigid, egocentric, defensively paranoid, power-oriented, interiorly distrustful, suspicious, hostile, and extremely avoidant of criticism. In general, he was very calm, but prone to periods of anxiety, tension, and somatic symptoms. The results of a House-Tree-Person [5] test concurred with the previously described findings. Based on the evaluations, a paranoid personality disorder was established. An intellectual quotient of 90, a verbal intellectual quotient of 92, and a performance intellectual quotient of 84 were reported.

Additional laboratory analyses showed: thyroid function test results of total and free triiodothyronine (T₃), total and free thyroxine (T₄), and thyroid-stimulating hormone (TSH) to be within normal ranges; a slight increase in total cholesterol levels with a value of 222 mg/dl; high-density lipoprotein (HDL) of 43 mg/dl and low-density lipoprotein (LDL) of 128 mg/dl; elevated triglycerides with a value of 234 mg/dl; no electrolyte abnormalities. His levels of glycemia, creatinine, transaminases, bilirubin, and testosterone were within normal ranges.

A total of 15 cells in metaphase were analyzed through conventional G-band karyotyping, reporting normal 46,XY. Due to the patient’s language characteristics as perceived by the examiner (verbiage), the affinity for music showed by the patient (multi-instrumentalist), complemented with the craniofacial dysmorphology, Williams–Beuren syndrome (MIM 194050) was suspected. A score of 8 was obtained when the Williams syndrome scoring table, which was presented at the 1994 Williams Syndrome Association Convention in San Diego, California, was applied; if the score ?3, fluorescence in situ hybridization (FISH) studies should be considered [6].

A 7 ml whole blood sample was extracted for analysis. To rule out aberrations related to the Williams–Beuren syndrome, a FISH was performed using a probe specific for the elastin gene (ELN; MIM 130160) in the Williams syndrome critical region on chromosome 7. In an individual who does not have the deletion, four signals will be detected, two signals on each chromosome 7. The signal at 7q11.23 is specific for the elastin gene, while the signal at 7q36 is the D7S427 chromosome 7 control probe which facilitates identification of the chromosome 7 homologs. In this study, 25 of 25 metaphase spreads and 65 of 66 interphase nuclei examined produced four signals indicating that there was no deletion in this region [see Additional file 1].

FISH analysis does not cover all genes involved in Williams–Beuren syndrome within region 7q11.23. Therefore, a whole genome single nucleotide polymorphism (SNP) array was performed. A second blood sample was extracted and DNA was analyzed using a CytoScan HD Microarray system (Affymetrix). This platform consists of 2.67 million markers (comprising ~1.9 million non-polymorphic copy number probes and ~750,000 SNP probes) at an average spacing of 1 probe every 800 base pairs (bp) throughout the entire human genome. This test compares the patient’s sample with control samples from the HapMap set of 270 individuals, and identifies genomic copy number variations and loss of heterozygosity regions. Chromosome Analysis Suite (ChAS) was utilized for the analysis of this microarray. SNP genotyping on this platform has the enhanced ability to identify long contiguous stretches of homozygosity (LCSH) and uniparental disomy; however, this assay cannot detect polyploidy, balanced rearrangements (for example, inversions and balanced chromosomal translocations), point mutations, and most mosaic conditions. All copy number changes were determined using the human genome build 19 (hg19/NCBI build 37).

Microarray CytoScan revealed 3191 kilo base pairs (kb) in a different region of chromosome 7 with International System for Human Cytogenetic Nomenclature (ISCN) array (hg19) 7q21.3 (93,389,222-96,579,845)x1. This deletion included SHFM1 syndrome region and 31 genes, of which 17 have Online Mendelian Inheritance in Man (OMIM) entries. The OMIM genes within this region are TFPI2 (MIM 600033), GNGT1 (MIM 189970), GNG11 (MIM 604390), BET1 (MIM 605456), collagen type 1 alpha-2 (COL1A2; MIM 120160), CASD1 (MIM 611686), sarcoglycan epsilon (SGCE; MIM 604149), PEG10 (MIM 609810), PPP1R9A (MIM 602468), PON1 (MIM 168820), PON3 (MIM 602720), PON2 (MIM 602447), ASB4 (MIM 605761), PDK4 (MIM 602527), DYNC1I1, solute carrier family 25 (citrin) member 13 (SLC25A13; MIM 603859), and SHFM1. The deletion did not include genes DLX5/6 [see Additional file 2].

Five maternal family members who showed mild mandibular hypoplasia and epicanthal fold were also analyzed. Microarray CytoScan did not report abnormalities in copy number of known or potential significance for the regions included on the chip. No cytogenetic analyses were performed on the patrilineal side of the patient. The father died before the patient was identified, and there were no available family members from the patrilineal side for genetic study.