Novel Compound Heterozygous Variants in the CDC6 Gene in a Russian Patient with Meier-Gorlin Syndrome

Figures & data

Figure 1 A girl with Meier-Gorlin syndrome: (A) – Failure to thrive, high forehead, short palpebral fissures, micrognathia; (B) - Bilateral microtia; (C) - Knees with absent patellae.

Figure 2 (A) - Molecular genetic results: the visualization of variants - c.230A>G, p.(Lys77Arg) and c.232C>T, p.(Gln78Ter) - with the Integrative Genomics Viewer (IGV). (B) - An amino acid sequence of the CDC6 gene in the region of the identified variants in different species. Lys77 is highly conserved across species. It is highlighted in the frame. (C) - 3D model of the interaction of the CDC6 protein with the CDK2/Cyclin A complex (PDB ID 2CCI): wild-type CDC6 interaction. (D) – 3D model of the interaction of the CDC6 protein with the CDK2/Cyclin A complex (PDB ID 2CCI): mutant protein CDC6 interaction. Color code: green chain – Cyclin A, red chain – CDC6, blue chain – CDK2; blue lines – hydrogen bonds, dark Orange lines – contacts.

Table 1 Clinical Characteristics of Patients with MGS

Clinical Characteristics	Previously Described^Citation1,Citation3,Citation7^–^Citation9,Citation35 (Patients with Different MGS Types)	The First Case of CDC6 MGS^Citation4 (Male, 4 y 6 m)	Our Patient (Female, 1 y 11 m)
Classical triad of clinical features
Short stature (<3%)	52/65, 80%	+	+
Microtia	63/68, 93%	+	+
Patellar hypoplasia/aplasia	52/62, 84%	+	+
Growth
IUGR (birth weight <3%)	35/36, 97%	+	+
Microcephaly	33/61, 54%	–	–
Craniosynostosis	15/68, 22%	N/A	N/A
Disproportionate stature	4/17, 24%	–	–
Facial features
Triangular face	N/A	+	+
Low-set ears	27/62, 44%	+	+
Posteriorly rotated ears	14/34, 41%	+	N/A
Convex nasal profile	14/30, 47%	-	-
Narrow nose	8/16, 50%	+	+
Microstomia	18/29, 62%	+	+
Full lips	30/40, 75%	+	N/A
Micro-/retrognathia	40/47, 85%	+	+
High arched palate	5/16, 31%	-	+
Exophthalmos	N/A	N/A	+
Neurological
Intellectual disability	3/49, 6%	±	-
Delayed motor development	12/50, 24%	±	+
Delayed speech development	10/50, 20%	-	-
Respiratory tract
Respiratory problems during infancy	16/33, 48%	+	+
Pulmonary emphysema	13/38, 34%	+	-
Tracheomalacia, laryngomalacia, bronchomalacia	11/34, 32%	-	-
Cardiac anomalies
	9/63, 14%	-	LV trabecula, patent foramen ovale
Gastrointestinal
Feeding problems during infancy	37/50, 74%	+	-
Nasogastric feeding/gastrostomy	18/49, 37%	-	-
Failure to thrive	22/53, 42%	+	+
Gastroesophageal reflux	16/49, 33%	+	-
Urogenital anomalies
Cryptorchidism/small testes, hypospadias, Micropenis	15/24, 63%	+	x
Clitoromegaly	5/37, 14%	x	+
Hypoplastic labia minora/majora	5/21, 24%	x	+
Renal anomalies	5/61, 8%	-	-
Musculoskeletal anomalies
Delayed bone age	14/22, 64%	+	+
Genu recurvatum	9/28, 32%	-	-
Contractures/club feet	7/30, 23%	-	-
Skin, nails
Prominent veins over nose and forehead		N/A	+
Thin skin		N/A	+
Hyperconvex nails		+	-
Other
	Dislocated joints, asymmetric limbs, hemivertebrae, bifid uvula, cleft palate, hypopigmentation, lipodystrophy, neonatal progeroid appearance, hearing loss, hypocorticolism	Osteochondroma, clinodactyly of the fifth fingers and fifth toes, submucous cleft palate	Hepatomegaly, arachnodactyly, lipodystrophy, partial alopecia, bronchopulmonary dysplasia, genu valgum, neonatal progeroid appearance

Notes: Designations: - means the sign is absent, + means the sign is markedly present, ± means the sign is moderate, N/A means data are not available, x – not applicable.

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