Table 1.
Clinical summary and variant description of Probands 1 and 2.
| Individual | Proband 1 | Proband 2 |
|---|---|---|
| Variant Information | ||
| Genomic change (GRCh37) | NC_000002.11:g.213900960_213921017dup | NC_000002.11:g.213914554C>G |
| cDNA change | NC_000002.11(NM_016260.3):c.406+540_574+13477dup | NM_016260.3:c.457G>C |
| Protein change | NP_057344.2:p.Gly136_Ser191dup | NP_057344.2:p.Gly153Arg |
| Exon(s) Affected | Exon 5 | Exon 5 |
| Variant Description | Exon 5 is duplicated in tandem, resulting in the inframe duplication of ZFs 2 and 3 and two linker sequences in the DNA binding domain | Missense variant is located in ZF2 in the DNA binding domain |
| Variant detection method | Trio genome sequencing– not detected by exome sequencing | Trio exome sequencing |
| Inheritance | De novo | De novo |
| General Information | ||
| Ancestry | European | European (Italian, Dutch) |
| Consanguinity | No | No |
| Sex | Female | Male |
| Pregnancy and Birth | ||
| Antenatal complications | • Unremarkable pregnancy • Normal growth and anatomy on ultrasounds at 18-20 weeks of gestation |
• Concern for gestational diabetes, treated with diet |
| Gestational age | • Spontaneous vaginal delivery at 38 weeks | • 35 weeks – caesarean section for breech presentation with premature rupture of membranes |
| Neonatal findings | • Abnormal results on Auditory Brainstem Response (ABR) test • Respiratory congestion due to excessive mucus – ongoing issue since birth • Excessive weight loss due to feeding difficulties related to cleft palate |
• Abnormal results on Auditory Brainstem Response (ABR) test • Respiratory distress after birth and was intubated/on supplemental oxygen for 8-weeks in the NICU |
| Birth weight (kg) | 2.86 (10th percentile) | 2.24 (30th percentile) |
| Most Recent Examination | ||
| Age | 4-6 years | 6-8 years |
| Weight (kg) | 15.5 (10th percentile) | 21.2 (10th percentile) |
| Height (cm) | 106.5 (25th percentile) | 119.6 (10th percentile) |
| Neurobiological Features | ||
| Developmental delay/ intellectual disability | • Global developmental delay affecting language, fine motor skills, and processing speed and emotional regulation | • Autism (CARS score 43 at 2.5y) – repetitive behaviors, head banging, poor eye contact, sensory-seeking/sensory-adverse behaviors, emotional outbursts |
| Motor development | • Delayed fine motor skills | • Borderline-mild delay in gross motor skills |
| Language and speech delay | • Receptive language is at the low end of normal for age • Expressive language is one year delayed • Phonological speech disorder |
• Significant language/communication delays • Nonverbal |
| Seizures | No | No |
| MRI scan | • Normal inner ear structures | • Cystic lesion within sella • Normal inner ear structures |
| Other Findings | ||
| Urological | No | • Hypospadias |
| Hearing/ENT | • Bilateral severe-to-profound sensorineural hearing loss • Chronic clear rhinorrhea and nasal congestion |
• Bilateral moderate sensorineural hearing loss • Mild asymmetric right bony choanal stenosis |
| Vision | • Blepharophimosis • Severe photophobia • Yellow crusting on eyelashes due to increased mucous production • Variable esotropia |
• Fusion of the right eyelid • Lagophthalmos • The cornea of both eyes had stellate epithelial and anterior stromal central opacity |
| Feeding | • Cleft palate causing feeding difficulties early in life – corrected by surgery • Feeding through NG tube starting 4 months of age until receiving a G-tube at 13 months of age • Mainly on oral diet starting 3 years of age |
• Cleft palate • Persistent feeding difficulties, received a G-tube at 3 months of age |
| Craniofacial differences | • Bitemporal narrowing • Ankyloglossia • Upturned nose • High forehead • Macrotia • Depressed nasal bridge |
• Brachycephaly • Midface hypoplasia • Narrow and long palpebral fissures • Short philtrum • Simplified ears • Prominent chin |
| Teeth | • Poor enamel • Thickened gums • Malaligned teeth |
• Dental caries |
| Skeletal | • No anomalies on examination and x-ray | • Juvenile osteochondrosis of the head of the left femur |
| Additional findings | • Athelia (absent nipples) • Mild bronchiectasis with increased lower airway secretions |
• Athelia (absent nipples) • Chronic lung disease - discoid atelectasis • Sleep problems |
| Immune Phenotype | ||
| Newborn screening for immunodeficiency | • Abnormal TREC assay – T cell lymphopenia | • Abnormal TREC assay – T cell lymphopenia |
| Susceptibility to infections | • Recurrent respiratory infections | • Recurrent pneumonia • Recurrent ear infections |
| Atopic disease | • Atopic dermatitis diagnosed at 10 months of age | • None noted |
| Autoimmune disease | • Autoimmune hemolytic anemia diagnosed at 2 months of age | • None noted |
| Additional findings | • Lymphopenia: low total CD4 and CD8 T cells • Normal IgA and IgM levels • Unable to accurately assess endogenous IgG production – patient on IVIG • Normal tetanus and diphtheria vaccine titers documented off IVIG |
• Lymphopenia: low total CD4, CD8 and B cells • Mildly low IgG with normal IgM and IgA • Poor Hib, tetanus, and S. pneumoniae vaccine titers |