ZNF292

Neurodevelopmental Disorders

A Role in Neurodevelopmental Disorders

Until recently there had been only a handfull of patients known to have ZNF292 mutations (de Light 2012, Popp 2017, Guo 2018). A recent publication has introduced 28 more families with known protien truncating mutations having a broad phenotype which generaly includes ASD, ADHD and or ID (Mirzaa 2019). The SFARI database now lists ZNF292 as a potential ASD candidate (https://gene.sfari.org/database/human-gene/ZNF292) with a score of 1 ("High Confidence").

The gnomAD V2.1.1 database has a computed pLI (probability of loss intolerance) at 1.0 implying it is important for an individual to have two functioning copies of this gene.

To date OMIM has no phenotype associated ZNF292.

Case Studies

de Ligt 2012
ZNF292 c.2828_2829del p.Leu943>Glnfs*5 and SCN2A c. 4193G>A p.Trp1398*

Phenotype: Moderate ID, behavior problems, epilepsy, sleep disturbances, stereotypic behavior

"The girl was born after a pregnancy complicated by hypertension. She had feeding problems and a delayed development from the start. From the age of six months she had epileptic seizures, although EEG remained normal. Since Rivatril treatment, the seizures disappeared. In addition, she received Melatonin for sleep disturbances. She could sit without support at one and a half years of age. A two and a half years she could speak a couple of words. She showed stereotypic behaviour. She had plagiocephaly, straight eyebrows, prominent antihelices and flat philtrum. 250K SNP array analysis, TCF4, MECP2 testing and metabolic screen was normal."

Note:This patient also has an SCN2A nonsense mutation. SCN2A is confirmed pathogenic and is a significant gene disrupted in NDD cases. The authors were thus unable to concluded whether or not the LGD mutation of ZNF292 was also pathogenic.

Popp, B. 2017
ZNF292 c.3066_3069del, p.(Glu1022Aspfs*3)
Phenotype: Developmental delay, constipation, feeding difficulties, hypothyreosis, short stature, facial dysmorphism

Gareth
ZNF292 c.1567C>T p.Gln523*
Phenotype: Developmental delay, regressive ASD, ADHD, stereotypic behavior, self-injurious behavior, sleep disturbances, gastroesophageal reflux disease, constipation, strabismus, hypotonia, facial dysmorphism (larger head, with smaller face, lower-set, square-shaped ears, higher arched palate), MRI findings (larger ventricles, thinner corpus callosum, thinner cerebrum). Biomedical findings (low ferritin levels, slightly elevated AST).

Mirzaa, G. 2019

de novo missense database Turner 2017 describes an online database of missense mutations from patients with NDD and lists eight ZNF292 mutations that are likely causative:

Missense Mutations from de-novo db (http://denovo-db.gs.washington.edu/denovo-db/)

PrimaryPhenotype	Position	Variant	FunctionClass	cDnaVariant	ProteinVariant	Exon/Intron
autism	87866910	CTGTG>CTG	intron	c.168+1434_168+1435del2	NA	intron1
autism	87925717	C>T	stop-gained	c.265C>T	p.(R89*)†	exon2
autism	87928346	C>G	missense	c.435C>G	p.(S145R)	exon4
control	87928346	C>G	missense	c.435C>G	p.(S145R)	exon4
autism	87935481	G>A	intron	c.538+7032G>A	NA	intron4
autism	87957456	G>A	intron	c.1020+2094G>A	NA	intron7
developmentalDisorder	87964419	C>T	missense	c.1072C>T	p.(R358C)	exon8
developmentalDisorder	87966075	C>A	missense	c.2728C>A	p.(L910I)	exon8
intellectualDisability	87966174	CTC>C	frameshift	c.2828_2829del2	p.(L943Qfs*5)	exon8
developmentalDisorder	87968567	AAATT>A	frameshift	c.5221_5224del4	p.(N1741Lfs*25)	exon8
congenital_heart_disease	87969631	AG>A	frameshift	c.6285del1	p.(K2096Sfs*36)	exon8

From SFARI Autism Genes Collection (https://gene.sfari.org/database/human-gene/ZNF292)

c.2490_2494dup	p.Ser832IlefsTer28	frameshift_variant	De novo		Wang T , et al. (2016)
c.265C>T	p.Arg89Ter†	stop_gained	De novo	Not simplex (positive family history)	Neale BM , et al. (2012)
c.3066_3069del	p.Glu1022AspfsTer3	frameshift_variant	De novo		Popp B , et al. (2017)

†Note: The R89* mutation has been attributed both to Neale 2012 and to De Rubeis 2014 but a specific reference to this mutation can not be found in either paper.

CNVs from Deciphering Developmental Disorders (decipher.sanger.ac.uk)

Variant GRCh37	Sex	Size	Pathogenicity/Contribution	Inheritance	Phenotype
6:72100590-97078142 Deletion	46XX	24.98 Mb	Unknown	Unknown	Abnormal joint morphology, Intellectual disability, Joint laxity, Low-set ears
6:79324861-88043414 Deletion	46XX	8.72 Mb	Unknown	De novo constitutive	2-3 toe syndactyly, Abnormality of the forehead, Abnormality of the kidney, Behavioral abnormality, Blepharophimosis, Cataract, Downslanted palpebral fissures, Epicanthus, Hearing impairment, High palate, Hypoplasia of the corpus callosum, Intellectual disability, Macrocephaly, Macrotia, Obesity, Short foot, Short palm, Umbilical hernia
6:84252330-97078182 Duplication	46XX	12.83 Mb	Pathogenic	Imbalance arising from a balanced parental rearrangement	Autism, Delayed speech and language development, High palate, Long eyelashes, Muscular hypotonia
6:83867406-88256494 Deletion	46XY	4.39 Mb	Unknown	Unknown	Camptodactyly of finger, Conductive hearing impairment, Congenital nystagmus, Inguinal hernia, Intellectual disability, Nystagmus, Scoliosis
6:70157311-98953422 Deletion	46XX	28.80 Mb	Pathogenic	Imbalance arising from a balanced parental rearrangement	Intellectual disability, Joint laxity
6:401016-170888348 Duplication	46XY	170.49 Mb	Unknown	Unknown	Arrhythmia, Depressed nasal bridge
6:87944463-88051322 Duplication	46XX	106.86 kb	Unknown	Inherited from parent with similar phenotype to child
6:86392937-87944492 Duplication	46XX	1.55 Mb	Unknown	Unknown
6:87277967-92573205 Deletion	46XX	5.30 Mb	Unknown	Unknown
6:84910384-88051463 Deletion	46XY	3.14 Mb	Unknown	Imbalance arising from a balanced parental rearrangement	Intellectual disability
6:84832770-88605452 Deletion	46XX	3.77 Mb	Unknown	De novo constitutive	Eczema, Hemiplegia, High-frequency hearing impairment, Mild global developmental delay, Partial anomalous pulmonary venous return, Posterior plagiocephaly, Recurrent respiratory infections, Sinus venosus atrial septal defect, Unsteady gait
6:84332578-90401145 Deletion	46XY	6.07 Mb	Likely pathogenic Full	Unknown	Dextrocardia, Eczema, Epicanthus inversus, Hypospadias, Inguinal hernia, Tracheomalacia, Umbilical hernia
6:86301318-91379453 Deletion	46XY	5.08 Mb	Pathogenic Full	De novo constitutive
6:82512470-90113793 Deletion	46XY	7.60 Mb	Pathogenic Full	Unknown	Calcaneovalgus deformity, Cleft palate, Glandular hypospadias, Hydronephrosis, Micrognathia
6:80938034-94091098 Deletion	46XY	13.15 Mb	Pathogenic	De novo constitutive
6:86514050-93689898 Deletion	46XY	7.18 Mb	Unknown	Unknown	Tracheoesophageal fistula
6:84293228-90174426 Deletion	46XX	5.88 Mb	Likely pathogenic	De novo constitutive	Anteriorly placed anus, Craniofacial asymmetry, Joint laxity, Short thorax
6:84956081-88452718 Duplication	46XY	3.50 Mb	Likely pathogenic Full	De novo constitutive	Language impairment, Microcephaly
6:87627887-90491265 Deletion	46XX	2.86 Mb	Uncertain Uncertain	Unknown
6:82770129-89584546 Deletion	46XX	6.81 Mb	Pathogenic Full	De novo constitutive