CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD), is a very rare

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

genetic condition characterised by

congenital heart defects A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

, intellectual disability and characteristic facial features. Those affected typically have motor and language delays, low muscle tone and

gastrointestinal dysmotility Intestinal pseudo-obstruction (IPO) is a clinical syndrome caused by severe impairment in the ability of the intestines to push food through. It is characterized by the signs and symptoms of intestinal obstruction without any lesion in the intestin ...

. Facial features include a wide nasal bridge, widely-spaced eyes, prominent,

low-set ears Low-set ears are a clinical feature in which the ears are positioned lower on the head than usual. They are present in many congenital conditions. Low-set ears are defined as outer ears positioned two or more standard deviations lower than the pop ...

, a flat nose tip and a small mouth. Less common features include congenital spinal abnormalities,

hearing loss Hearing loss is a partial or total inability to Hearing, hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to Language ...

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

. The syndrome is caused by a mutation in the '' CDK13''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, which encodes the

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

cyclin-dependent kinase 13.

Cyclin-dependent kinases Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...

are

protein kinases A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fun ...

, which are critical for regulating

DNA transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...

for

cell differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...

. CDK13 promotes

expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, o ...

of genes involved in various developmental processes, and these processes are disrupted or not completed when the gene is mutated. The syndrome is diagnosed when genetic testing confirms a mutation in ''CDK13''. Treatment centres around the symptoms.

Medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

or, in severe cases,

gastrostomy Gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression. Typically this would include an incision in the patient's epigastrium as part of a formal operation. It can be perfor ...

can be used for the gastrointestinal dysmotility. Speech therapy as early as possible or assistive communication devices can aid language development. The prognosis is not certain as of yet, due to the lack of known patients, however a few patients in mid-adulthood have been identified. , at least 44 individuals with the condition had been identified and studied. Mutations in ''CDK13'' were first identified as pathogenic in a 2016 cohort study, and the disorder was first outlined by Bostwick et al. in 2017, who also established the name CHDFIDD.

Signs and symptoms

Most individuals with CDK13-related disorder have

, typically an

atrial The atrium ( la, ātrium, , entry hall) is one of two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular valves. There are two atr ...

ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...

. Those with the disorder typically have a characteristic facial appearance which includes a wide nasal bridge, widely-spaced eyes, upslanted eyelids,

epicanthic folds An epicanthic fold or epicanthus is a skin fold of the upper eyelid that covers the inner corner (medial canthus) of the eye. However, variation occurs in the nature of this feature and the possession of "partial epicanthic folds" or "slight ...

, high-arched eyebrows, prominent,

, a flat nose tip and a small mouth with a small upper lip. In some of those affected, the syndrome causes curly hair. The facial appearance has been noted to resemble that of

Kabuki syndrome Kabuki syndrome (also previously known as Kabuki-makeup syndrome (KMS) or Niikawa–Kuroki syndrome) is a congenital disorder of genetic origin. It affects multiple parts of the body, with varying symptoms and severity, although the most common is ...

. The syndrome typically results in intellectual disability, including motor and language delays. Some individuals have had

agenesis of the corpus callosum Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres ...

aplasia Aplasia (; from Greek ''a'', "not", "no" + ''plasis'', "formation") is a birth defect where an organ or tissue is wholly or largely absent. It is caused by a defect in a developmental process. Aplastic anemia is the failure of the body to produ ...

of the

cerebellar vermis The cerebellar vermis (from Latin ''vermis,'' "worm") is located in the medial, cortico-nuclear zone of the cerebellum, which is in the posterior fossa of the cranium. The primary fissure in the vermis curves ventrolaterally to the superior ...

. This can sometimes manifest with symptoms of

autism spectrum disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...

. Low muscle tone and

strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

are also common. A few patients have had

microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...

and

. Affected individuals tend to have

dysautonomic Dysautonomia or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and blood vessels. Dysautonomia has ...

symptoms of

, which can include

gastroesophageal reflux Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

and trouble swallowing. A few of those affected have had ear problems such as

sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...

or recurrent

ear infections Otitis is a general term for inflammation or infection, inner ear infection, middle ear infection of the ear, in both humans and other animals. When infection is present, it may be viral or bacterial. When inflammation is present due to fluid bui ...

, and a few individuals have had congenital spinal abnormalities including fused vertebrae or

spina bifida Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, me ...

as well as

scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

Cause

The syndrome is caused by a mutation in one of the two copies of the gene '' CDK13'', which encodes the protein cyclin dependent kinase 13.

are

, which have an essential function in the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

and the transcription of DNA. This is specifically through

protein phosphorylation Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...

, which functions to turn off or on certain proteins, allowing

and the progression of the normal developmental processes. A mutation in one of the two copies of these genes results in some proteins not being formed correctly and therefore some developmental processes being disrupted or not completed. Specifically, CDK13 appears to phosphorylate

RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryoti ...

and enable it to carry out transcription of genes on DNA. It appears to largely do this when RNA polymerase II is transcribing certain genes involved in promoting cell development. Mutations in ''CDK13'' that have been identified in individuals with this disorder have mostly been

missense mutations In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense mu ...

(single

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

changes) that have changed the amino acid structure of the otherwise highly conserved (little-changed)

protein kinase domain The protein kinase domain is a structurally conserved protein domain containing the catalytic function of protein kinases. Protein kinases are a group of enzymes that move a phosphate group onto proteins, in a process called phosphorylation. This ...

of the gene, leading to structural changes that affect the operation of this critical protein. The most commonly identified mutations are those that change the 842nd amino acid of the protein, an

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

(Asn), to a

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

(Ser) or an

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

(Asp), but many others have been identified. Different mutations, depending on how much they reduce the kinase functionality of the gene, have resulted in different severities of the syndrome. Those with total activity-eliminating mutations have, for example, had microcephaly. Mutations in both copies of ''CDK13'' are embryonic lethal in mice. Mice who have had both of their copies of ''CDK13''

knocked out A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...

do not survive past the 16th day of

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

due to heart failure, as the heart has significantly fewer

myocytes A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

and less

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...

, with less expression of

myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin ...

. All organs are smaller and less developed, and the embryo is reduced in size.

Diagnosis

The condition is generally diagnosed after genetic testing confirms ''CDK13'' as mutated, although the condition may be suspected based on the symptoms. Methods to detect the mutation include

whole exome sequencing Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subset ...

and panel testing, in which a selection of potential genes involved are sequenced. The mutation can be confirmed by

Sanger sequencing Sanger sequencing is a method of DNA sequencing that involves electrophoresis and is based on the random incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. After first being developed by Frederi ...

Treatment

Treatment centres around the symptoms.

Atrial The atrium ( la, ātrium, , entry hall) is one of two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular valves. There are two atr ...

ventricular septal defects A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right Ventricle (heart), ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular sep ...

are usually treated with observation but can be surgically corrected in severe cases. Prokinetic medication can be used to promote gastric emptying. If the gastric dysmotility is too severe for adequate intake, a

can be performed. Speech therapy as early as possible or assistive communication devices can aid in language development.

Prognosis

The prognosis is not certain as of yet, as most of the individuals discovered and studied have been children, however a few patients in mid-adulthood have been identified.

Epidemiology

The prevalence is not yet known, as the disorder was only recently defined. Beginning with Bostwick et al.'s report in 2017, at least 44 individuals with the condition have been identified and studied .

History

Mutations in ''CDK13'' were first identified as pathogenic in 2016, when they were identified in 7 individuals from a large cohort of 1,891 patients with congenital heart defects in a study by Sifrim et al. Mutations in ''CDK13'' were then found again in 2017 in 11 individuals from an even larger cohort of 4,293 patients from the UK and Ireland with developmental delay by McRae et al., as part of the UK Deciphering Developmental Disorders (DDD) cohort study. The disorder was first established and outlined by Bostwick ''et al,'' (2017) (9 patients), who also established the term ''congenital heart defects, dysmorphic facial features and intellectual developmental disorder'' (''CHDFIDD''). Later work by Hamilton et al. (2018) (16 patients), Uehara et al. (2018) (3 patients) and van den Akker et al. (2018) (15 patients) identified and studied additional patients.

Gallery

References

External links

{{Medical resources, DiseasesDB=, ICD10=, ICD9=, ICDO=, OMIM=617360, OMIM_mult=, MedlinePlus=, eMedicineSubj=, eMedicineTopic=, MeshID=, GeneReviewsNBK=NBK536784, GeneReviewsName=CDK13-Related Disorder, Orphanet=, Orphanet_mult= Rare genetic syndromes Syndromes affecting the gastrointestinal tract Syndromes affecting head size Syndromes affecting the heart Syndromes affecting bones Syndromes affecting the nervous system