TABLE 2.
Summary of clinical and molecular features for individuals with microcephaly and novel CCND2 variants
| LR19-002 | LR19-392 | LR20-198 m | LR20-198a1 | LR20-198a2 | ||
|---|---|---|---|---|---|---|
| Genetic testing | Identified variant | CCND2: NM_001759.4: c.416_419dupGGGA, p.L141GfsX19 | CCND2: NM_001759.4:c.305delG, p.G102VfsX17 | CCND2: NM_001759.4:c.544C>T, p.Q182X(het) | ||
| Molecular methods and other molecular findings [inheritance] | Exome sequencing; GBA (c.882T>G, p.H294Q), het, VUS [pat]; TENM1 (c.679 C>A, p.P227T), VUS, [mat] | NGS panel; no | Array CGH, targeted sequencing, arr 18q12.3 (37.877.518–37.961.503)x3 (hg18) | Exome sequencing, Array CGH, arr 18q12.3 (37.877.518–37.961.503)x3mat (hgl8) | Array CGH, Targeted sequencing, arr 8q23.1 (106.455.702–107.566.961) x3pat,18q12.3 (37.877.518–37.961.503)x3mat (hgl8) | |
| Demographics | Sex | M | F | F | M | F |
| Age at last assessment | 7m | 12y2m | 30y | 12y11m | 6y8m | |
| Ethnicity | ND | ND | Caucasian (Germany) | Caucasian (Germany) | Caucasian (Germany) | |
| Notable family history | Non-consanguineous, conceived via intrauterine insemination, family history unremarkable | Non-consanguineous, family history unremarkable | Father has boderline ID, short stature and microcephaly without genetic diagnosis | See LR20-198 m. One sibling and two maternal half siblings show normal OFC and normal development and do not carry CCND2 variant | See LR20-198a1 | |
| Pregnancy and birth | Pregnancy | G1P1 mother, suspected preeclampsia, vaginal bleeding, IUGR at 32-33gw | G2P2, IUGR at end of second trimester | G1P1 | G1P1 | G4P3 |
| Gestational age (weeks/days) | 35 + 6 | 39 + 0 | ND | 38 + 5 | 37 + 5 | |
| Birth weight (%le/z-score) | 1870 g (2.13%, −2.05 SD) | 2320 g (3%, −1.8 SD) | ND | 2900 g (10–25%, −1.2 SD) | 2480 g (3%, −1.8 SD) | |
| Birth length (%le/z-score) | 43.5 cm (3%, −1.8 SD) | 46 cm (3–10%, −1.5 SD) | ND | 49 cm (25–50%, −1 SD) | 47 cm (10–25%, −1.3 SD) | |
| Birth head circumference (%le/z-score) | 30.5 cm (3–10%, −1–2 SD) | 32 cm (2%, −2 SD) | ND | 29.5 cm (<1%, −4.3 SD) | 32 cm (2%, −2 SD) | |
| Growth | Weight at last assessment (%le/z-score) | 6.1 kg (0.48%, −2.6 SD) | 25.50 kg (<0.1%, −2.8 SD) | 85 kg (95%, +1.68 SD) | 34.2 kg (5%, −1.7 SD) | 15.2 kg (<1%, −2.8 SD) |
| Height at last assessment (%le/z-score) | 64.5 cm (5%, −1.6 SD) | 140.5 cm (7%, −1.4 SD) | 150 cm (2%, −2 SD) | 144.5 cm (7%, −1.5 SD) | 111 cm (2%, −2 SD) | |
| Head circumference at last assessment (%1e/z-score) | 40.2 cm (<1%, −3.1 SD) | 48 cm (<1%, −4.3SD) | 51 cm (<1%, −3.1 SD) | 48 cm (<1%, −4.2 SD) | 45.2 cm (<1%, −5 SD) | |
| Growth failure | Yes | Yes | Yes | No | Yes | |
| Neurologic findings | Degree of developmental delay or ID | N.E. | Mild | Mild | Mild | |
| Age–1st walked | N.E. | 13 m | 2 years | 12 month | 11 month | |
| Age–1st words | N.E. | Unknown | Unknown | Unknown | ||
| Speech delays | N.E. | Yes | Unknown | Yes (with 3 years less than 100 words and two-word-sentences) | Yes | |
| Seizures | No | No | No | No | No | |
| EEG findings | N.E. | N.E. | N.E. | normal | yes, among others occipital epileptic potentials | |
| Tone abnormalities | Hypotonia | No | N.E. | No | No | |
| Brain MRI findings | Microcephaly with a mildly simplified gyral pattern | Microcephaly with a mildly simplified gyral pattern | N.E. | Normal | Normal | |
| Autism | N.E. | No | N.E. | No | No | |
| ADHD | N.E. | Yes, mild | N.E. | Suspected | N.E. | |
| Other behavioral issues | N.E. | No | aggressive, impulsive and antisocial behavior | recurring (breath-holding spells), impusive behavior, reduced interaction with peers | ||
| Other neurologic findings | No | No | No | No | No | |
| Formal developmental or autism assessments | N.E. | Special school | Attended a special school | Attended a special school | Bayley II (23 month): in the lower standard range | |
| Other findings | Dysmorphic facial features | Mild right occipital flattening | Large ears, short philtrum, incomplete single transverse right palmar crease | Sloping forehead, broad nasal tip, upslanting palpebral fissures, long philtrum, thin upper lip vermilion | Sloping forehead, broad nasal base, broad nasal tip, long philtrum, thin upper lip vermilion | Sloping forehead, broad nasal tip |
| Heart | N.E. | N.E. | N.E. | N.E. | N.E. | |
| Eyes | N.E. | Mild myopia | N.E. | N.E. | Normal | |
| Urogenital system | N.E. | N.E. | N.E. | N.E. | N.E. | |
| Skeletal | N.E. | Bone age delayed at 2y10m, normalized later | N.E. | Pes planus | Talus obliqus and pes planus unilateral | |
| GI | N.E. | N.E. | N.E. | N.E. | Nutritional difficulties | |
| Other medical issues | Mild motor delays at birth, responded well to physical therapy | No | Bilateral inguinal hernia after birth | Asphyxia, anchyloglossia | Respiratory adaptation disorder with CPAP-therapy, failure to thrive | |
Notes: The table summarizes the clinical features, growth data, and family history for the five individuals with proximal CCND2 frameshift or stop-gain variants.
Abbreviation: N.E., not evaluated.