Skraban-Deardorff Syndrome

10/08/2022

Meet some of our joyful children and their families as they describe how Skraban-Deardorff Syndrome has impacted their lives.

Meet some of our joyful children and their families as they describe how Skraban Deardorff Syndrome has impacted their lives.

24/03/2022

12/08/2019

Gene Reviews of Skraban-Deardorff syndrome

WDR26-related intellectual disability (ID) is characterized by developmental delay / intellectual disability, characteristic facial features, hypotonia, epilepsy, and infant feeding difficulties. To date 15 individuals, ages 24 months to 34 years, have been reported. Developmental delay is present i...

07/12/2018

Dear Reader,

Every gene in our body has two copies, but imagine trying to play a guitar with only half of the guitar strings.

In 2017 doctors at Children’s Hospital of Philadelphia (CHOP), in partnership with a network of doctors worldwide, discovered a mutation on the gene WDR26.

The condition was named Skraban-Deardorff Syndrome, after the lead doctors who discovered it at CHOP. This mutation happens when only one of the two copies of the gene is properly working. It generates seizures, overall development delays (especially in speech), intellectual disability, and some specific facial features. The WDR26 gene was recently discovered and its role in the human body is still unknown. Since its’ discovery, 45 people around the world (mostly children) have been diagnosed with the WDR26 mutation. What we, the WDR26 families, do know is that we are very fortunate to have children who are always happy, affectionate and have smiles that light up the world.

The most promising way to help these children improve their quality of life and achieve their full potential would be to enhance the copy of the WDR26 gene that is functioning properly.

With that goal, Children’s Hospital of Philadelphia will conduct a study. The results from this research can make a huge difference in our children’s lives. We are committed and excited to support this research further, but need to raise funds and increase awareness in order to reach our goal.

You can contribute directly on the link below to Children’s Hospital of Philadelphia in a dedicated account to the WDR26 research (all international credit cards and Pay Pall are also accepted).
If you are a US taxpayer, the donation is also tax-deductible (receipt will be sent by email).

Link to donation site:
https://chop.donordrive.com/index.cfm?fuseaction=donorDrive.personalCampaign&participantID=64088

The WDR26 mutation is part of our children's identity, but any improvement will mean more than you know, and allow them to better enjoy the music of life.

Thanks for sharing your hope with us.

Help to support me and Children's Hospital of Philadelphia Foundation through my fundraising page!

17/10/2018

Learn about Skraban-Deardorff syndrome from the experts at CHOP who discovered the condition. Learn about the causes, signs and symptoms, treatment, follow-up are and more.

12/06/2018

Changes in the gene WDR26

SKRABAN-DEARDORFF SYNDROME; SKDEAS

INTELLECTUAL DISABILITY WITH SEIZURES, ABNORMAL GAIT, AND DISTINCTIVE FACIAL FEATURES

There is evidence that Skraban-Deardorff syndrome (SKDEAS) is caused by heterozygous mutation in the WDR26 gene (617424) on chromosome 1q42.

▼ Description
Skraban-Deardorff syndrome (SKDEAS): An autosomal dominant syndrome. SKDEAS is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development with variable intellectual disability with delayed speech or no speech, early-onset febrile and non-febrile seizures, abnormal gait, and facial dysmorphism Characteristic dysmorphic facial features comprising coarse facies with a prominent maxilla and upper lip revealing the upper gingiva, widely-spaced teeth, and a broad nasal tip (summary by Skraban et al., 2017).

▼ Clinical Features
Skraban et al. (2017) reported 15 unrelated individuals, ranging in age from 24 months to 34 years, with a syndromic form of intellectual disability apparent since infancy. All patients had global developmental delay that varied in severity from mild to severe, and all had some form of speech delay, including several with absent speech between 4 and 8 years of age. Motor delay was common, with delayed sitting, crawling, and walking, and 9 patients had mild hypotonia. Walking was acquired between 17 months and 3 years, although most had an abnormal spastic, stiff, or wide-based gait. All patients had onset of seizures in infancy or in childhood, although the seizure type varied and included febrile, nonfebrile, tonic-clonic, absence, and Rolandic seizures. Nine patients had minor variable structural brain abnormalities, including dilated ventricles, thin corpus callosum, white matter volume loss, and pineal cysts; opercular dysplasia and pachygyria was found in 1 patient. However, several patients had normal brain imaging. The patients had a distinctive gestalt with coarse facial features and common abnormalities, including prominent maxilla and upper lip (13 patients), wide mouth (10), abnormal gingiva (9), widely spaced teeth (13), full cheeks in childhood (11), large irises with rounded palpebral fissures (10), strabismus and/or amblyopia (9), broad or full nasal tip (11), and cupid bow of the lip (11). Less common features included anteverted nares (8), depressed nasal bridge (5), sparse lateral eyebrows (6), and mild micrognathia (5). Many patients had nonspecific gastrointestinal abnormalities, mainly constipation, gastric reflux, or poor feeding, and several had recurrent otitis media in the absence of an immune disorder. Rare features included cardiac defects and minor skeletal anomalies. The patients had a happy demeanor overall; some had repetitive behaviors or autistic features. Skraban et al. (2017) noted that the phenotype in these patients showed overlap with that of chromosome 1q41-q42 deletion syndrome (612530).

▼ Molecular Genetics
In 15 unrelated patients with Skraban-Deardorff syndrome, Skraban et al. (2017) identified 15 different de novo heterozygous mutations in the WDR26 gene (see, e.g., 617424.0001-617424.0006). There were 5 frameshift, 5 nonsense, 1 splice site, and 4 missense mutations. Analysis of patient cells from 3 patients, including 2 with truncating mutations (617424.0002 and 617424.0004) and 1 with a missense mutation (D284N; 617424.0005), showed that the truncating mutations resulted in significantly decreased mRNA and protein levels and the missense mutation resulted in slightly decreased mRNA and protein levels, suggesting haploinsufficiency as the pathogenic mechanism. Further functional studies and studies of the other variants were not performed. Skraban et al. (2017) postulated that reduced expression of WDR26 may alter multiple signaling pathways and cellular mechanisms. The patients, all of whom were of European descent or from the United States, were ascertained from several different large patient cohorts and gene repository databases; all mutations were found by trio-based exome sequencing. The frequency of WDR26 mutations was about 1 in 2,000 for all exome analyses and about 1 in 1,500 for individuals with intellectual disability, suggesting that this disorder may not be uncommon. Skraban et al. (2017) suggested that WDR26 may be the likely candidate gene whose haploinsufficiency is the cause of 1q41-q42 deletion syndrome, as it lies within the deleted region in most of those patients.

▼ CLINICAL SYNOPSIS

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Coarse facies
- Prominent maxilla
- Full cheeks
- Micrognathia, mild
Ears
- Otitis media, recurrent
Eyes
- Large appearing irises
- Rounded palpebral fissures
- Sparse lateral eyebrows
- Strabismus
- Amblyopia
Nose
- Anteverted nares
- Depressed nasal bridge
- Full nasal tip
Mouth
- Prominent upper lip
- Cupid bow
- Abnormal gingiva
Teeth
- Widely spaced teeth
ABDOMEN
Gastrointestinal
- Constipation
- Gastric reflux
- Poor feeding
MUSCLE, SOFT TISSUES
- Hypotonia
NEUROLOGIC
Central Nervous System
- Global developmental delay
- Intellectual disability, variable severity
- Poor or absent speech
- Delayed walking
- Wide-based gait
- Stiff gait
- Spastic gait
- Seizures, variable types
- Brain imaging may show abnormalities
- Dilated ventricles
- Thin corpus callosum
- White matter volume loss
- Pineal cysts
Behavioral Psychiatric Manifestations
- Happy demeanor
- Repetitive behaviors
- Autistic features
MISCELLANEOUS
- Onset in infancy
- Variable severity
- De novo mutation
MOLECULAR BASIS
- Caused by mutation in the WD repeat-containing protein 26 gene (WDR26, 617424.0001)

▼ CHROMOSOMAL LOCATION
Cytogenetic Location: 1q42.11-q42.12, which is the long (q) arm of chromosome 1 between positions 42.11 and 42.12

Molecular Location: base pairs 224,385,143 to 224,434,299 on chromosome 1 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

▼ REFERENCES
Skraban, C. M., Wells, C. F., Markose, P., Cho, M. T., Nesbitt, A. I., Au, P. Y. B., Begtrup, A., Bernat, J. A., Bird, L. M., Cao, K., de Brouwer, A. P. M., Denenberg, E. H., and 28 others. WDR26 haploinsufficiency causes a recognizable syndrome of intellectual disability, seizures, abnormal gait, and distinctive facial features. Am. J. Hum. Genet. 101: 139-148, 2017. [PubMed: 28686853, related citations]

SKRABAN-DEARDORFF SYNDROME·13. DECEMBER 2017

03/06/2018

Are you a parent and searching for a community to discuss and share knowledge about the Skraban-Deardorff Syndrome ?
Then search no more. There is a special page for parents with kids living with this syndrome on Facebook. Search on Facebook for: wdr26-related diagnoses

You can also contact Katie Grand at Children's Hospital of Philadelphia.

Katie Grand is a genetic counselor in the Division of Human Genetics at The Children's Hospital of Philadelphia.

09/12/2017

Cara Skraban, MD, is an attending physician with the Division of Human Genetics and the Roberts Individualized Medical Genetics Center at Children’s Hospital of Philadelphia.

CREDIT: Children's Hospital of Philadelphia

09/12/2017

New genetic syndrome identified; may offer some answers for puzzled parents

CHOP researchers describe WDR26 haploinsufficiency syndrome

CHILDREN'S HOSPITAL OF PHILADELPHIA

Researchers have identified a rare genetic syndrome characterized by intellectual disability, seizures, an abnormal gait and distinctive facial features. The scientists pinpointed variants in the WDR26 gene as causes for this distinctive, yet unnamed condition. Their early research provides initial information for counseling patients and families coping with uncertainties for children with the rare, poorly recognized condition.

"Our study identifies 15 individuals now known to have this recognizable syndrome, but we expect that as this information reaches the medical community, more patients will be recognized," said study leader Matthew A. Deardorff, MD, PhD, a pediatric geneticist at Children's Hospital of Philadelphia (CHOP). "Our studies are very much in the early stage, but as we continue to gain more clinical and scientific knowledge about this condition, we will be able to better explain to parents what to expect."

Deardorff, first author Cara M. Skraban, MD, also of CHOP, and co-authors from medical centers in six countries published their research today in the American Journal of Human Genetics.

"Prior to our identification of individuals with changes in this gene, it was not even listed in some of the most commonly used databases," said Deardorff. "The notable efforts by our colleagues here in the Division of Genomic Diagnostics at CHOP, and at key labs in the Netherlands and Maryland, helped us to make this discovery possible."

The scientists reported on 15 individuals, ranging from two years old to 34 years old. All the patients had developmental delays (ranging from mild to severe), seizures, and similar facial features (such as wide mouths, prominent upper lip and gums, full cheeks and a broad nasal tip). Many had subtle abnormalities in their gait. All 15 had de novo (new) mutations--those arising in a single egg or s***m that developed into the affected patient, but did not occur in the patient's parents.

The group at CHOP, along with global collaborators, is working energetically to understand the syndrome's functional details and underlying mechanisms. Although the specifics are still under investigation, the authors suggest that haploinsufficiency (reduced expression) of the WDR26 gene alters multiple signaling pathways and cell functions to produce features of the syndrome.

"There is no good laboratory assay yet for the effects of these mutations, but clinicians may notice facial differences or other signs, and would typically order exome sequencing, which would diagnose this syndrome," said Deardorff. "If testing confirms this diagnosis, we advise parents that seizures may occur, which are usually treatable with standard medicines. It may be possible that early intervention with special education can help address a child's intellectual disability, although we do not yet have enough clinical data to develop full guidelines for medical management."

Deardorff added that CHOP has started a patient registry to compile clinical data on this rare condition (see WDR26@email.chop.edu), and that this data collection may offer a resource for families interested in contacting each other to share information and support. He added, "This discovery is just the first step in understanding why changes in WDR26 cause intellectual disability and seizures. With further investigation, our goal is to better understand the biology and identify specific treatments for these children."

# # #

Institutional funds from the Children's Hospital of Philadelphia Research Institute and CureKids New Zealand supported this research. Co-authors were from the U.S., New Zealand, France, the U.K., the Netherlands and Germany.

Cara M. Skraban et al, "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features," American Journal of Human Genetics, published July 6, 2017 http://doi.org/10.1016/j.ajhg.2017.06.002

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 546-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

09/12/2017

Matthew A. Deardorff, MD, PhD, is a pediatric geneticist at Children's Hospital of Philadelphia.

CREDIT: Children's Hospital of Philadelphia

08/12/2017

Early research provides the initial information used for counseling patients and families coping with the uncertainties associated with the rare and poorly recognized condition. (Photographs: Children's Hospital of Philadelphia)