17q12 microdeletion syndrome

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17q12 microdeletion syndrome
Other names17q12 deletion syndrome
Human male karyotype high resolution - Chromosome 17.png
The human karyotype with chromosome 17 highlighted
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Kidney problems, diabetes, reproductive anomalies, neuroatypicality
Usual onsetConception
DurationLifelong
CausesChromosome microdeletion
Diagnostic method Fluorescence in situ hybridization

17q12 microdeletion syndrome, also known as 17q12 deletion syndrome, is a rare chromosomal anomaly caused by the deletion of a small amount of material from a region in the long arm of chromosome 17. It is typified by deletion of the HNF1B gene, resulting in kidney abnormalities and renal cysts and diabetes syndrome. It also has neurocognitive effects, and has been implicated as a genetic factor for autism and schizophrenia.

Contents

17q12 microdeletion syndrome is not to be confused with 17q12 microduplication syndrome, caused by the addition of genetic material in the same region from which it is removed in the microdeletion, or 17q21.31 microdeletion syndrome, another name for Koolen–De Vries syndrome.

Presentation

17q12 microdeletions have a variable phenotype, ranging from few or no symptoms to severe disability. The condition is thought to be underdiagnosed, and cases with milder phenotypes may not reach clinical attention unless they have an affected child themselves. [1] [2] The most characteristic symptom is renal cysts and diabetes syndrome (RCAD), also known as "type 5 diabetes", which is caused by deletion of the associated HNF1B gene in the region. [3] RCAD is associated with kidney abnormalities and a characteristic form of diabetes that causes atrophy of the pancreas. However, some people with 17q12 microdeletions have normal renal function. [2] RCAD is diagnosed in approximately 40% of people with 17q12 microdeletions, usually prior to age 25, while kidney abnormalities more broadly occur in approximately 85-90%. [4]

People with 17q12 microdeletions have a characteristic facial phenotype, albeit a subtle one not usually obvious in daily life. Macrocephaly is common, along with high arched eyebrows, flattening of the malar region, and epicanthic folds. [4] Pathological short stature is possible, and a characteristic "short and stocky" body shape occurs in many cases. [1]

17q12 microdeletions are associated with neurocognitive and developmental involvement of variable severity. Some have mild to moderate intellectual disability; however, such impairment is not universal. [5] [6] Average intelligence is in the average to low average range. [7] Speech delay is common, regardless of intellectual functioning. The most striking association between 17q12 microdeletions and neurodevelopment is the raised prevalence of autism spectrum disorder, with significant increases in both diagnosis and subclinical autistic traits. [7] [8] 17q12 microdeletions have been implicated as one of the major genetic causes of high-functioning autistic spectrum disorders. [1] Schizophrenia is also a significant psychiatric complication of 17q12 microdeletion syndrome. 17q12 microdeletions are estimated to occur in approximately 1 in 1,600 people with schizophrenia, compared to an estimation of below 1 in 50,000 in the general population. [8] Epilepsy, usually mild, occurs in approximately one-third of cases. [6]

Reproductive system anomalies are associated with 17q12 microdeletions, particularly in females. 17q12 microdeletions have been linked to uterine malformations, most frequently Müllerian agenesis, where the uterus and part of the vaginal canal are absent. [4] [9]

Autosomal dominant inheritance Autosomal dominant - en.svg
Autosomal dominant inheritance

Causes

17q12 microdeletion syndrome is an autosomal dominant disorder, where one copy of the relevant mutation is enough to cause the condition. Most cases are de novo, or spontaneous mutations that do not occur in the proband's parents; [10] approximately 75% are de novo, while 25% are inherited. [4] People with 17q12 microdeletions who have normal fertility have a 50% chance of passing the deletion down to their offspring. [1] Environmental factors have not been implicated in the syndrome. [1]

Diagnosis

Like other chromosomal microdeletions, 17q12 microdeletion syndrome is diagnosed via fluorescence in situ hybridization. [11] Traditional karyotyping, used to diagnose major chromosomal disorders such as aneuploidy, is rarely sensitive enough to detect microdeletions. [11]

Treatment

As the underlying 17q12 microdeletion is an innate genetic disorder, it cannot by itself be treated. Rather, treatment is symptomatic and supportive. The high prevalence of kidney disease indicates routine monitoring of renal function, particularly in people taking potentially nephrotoxic medications such as lithium. The comorbidities involved in 17q12 microdeletion syndrome require caution in medical treatment; for instance, the increased risk of diabetes requires strict monitoring for post-transplantation diabetes mellitus in kidney transplant patients, as does the risk of weight gain and diabetes from neuroleptic drugs in those with a mental health diagnosis. [4]

Epidemiology

The prevalence of 17q12 microdeletion syndrome is unknown, and it is likely to be underdiagnosed. 17q12 microdeletions are estimated to occur in approximately 1 in 600 people on the autism spectrum and 1 in 1,600 with schizophrenia, but are far rarer in the general population. [8] General prevalence is estimated to be between 1 in 14,000 [4] and 1 in 62,500. [12]

In addition to the increased prevalence in autism and schizophrenia, some other clinical populations have increased prevalence of 17q12 microdeletion syndrome. The condition occurs in approximately 2% of those with congenital kidney abnormalities and 3-6% of women with Müllerian agenesis. [4] It is one of the ten most common microdeletions amongst children with idiopathic developmental delay. [1]

Microduplication

17q12 microduplication syndrome is far rarer than the corresponding microdeletion, estimated to occur roughly one-fifth as frequently as 17q12 microdeletion syndrome. Due to its rarity and the overlap between their phenotypes, 17q12 microduplications are usually discussed as an adjunct to microdeletions. [3] Like the microdeletion syndrome, the microduplication syndrome has a broad phenotypic range, ranging from asymptomatic to profound disability; intellectual disability is frequently but not always more severe than the microdeletion, while physical health is often better. [13] [14] Epilepsy is a frequent finding. A case of sex reversal has been reported. [13] While autism comorbid with 17q12 microduplication has been reported, it appears far rarer than in the microdeletion. [15] Physical anomalies associated with 17q12 microduplication syndrome include syndactyly, microcephaly, epicanthic folds, and thick eyebrows or a unibrow. [13] [14] The 17q12 microduplication appears to have a low penetrance, as many cases are inherited from asymptomatic parents. [13]

See also

Related Research Articles

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Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype. Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product. Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.

Smith–Magenis syndrome (SMS), also known as 17p-microdeletion syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, difficulty sleeping, and numerous behavioral problems such as self-harm. Smith–Magenis syndrome affects an estimated between 1 in 15,000 to 1 in 25,000 individuals.

<span class="mw-page-title-main">Heritability of autism</span> The rate at which autism is inherited

Autism has multiple causes. This article focuses on heritable causes. The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.

<span class="mw-page-title-main">22q13 deletion syndrome</span> Rare genetic syndrome

22q13 deletion syndrome, known as Phelan–McDermid syndrome (PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome. The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions. The requirement to include SHANK3 in the definition is supported by many but not by those who first described 22q13 deletion syndrome.

<span class="mw-page-title-main">2q37 deletion syndrome</span> Medical condition

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<span class="mw-page-title-main">Renal cysts and diabetes syndrome</span> Medical condition

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Potocki–Lupski syndrome (PTLS), also known as dup(17)p11.2p11.2 syndrome, trisomy 17p11.2 or duplication 17p11.2 syndrome, is a contiguous gene syndrome involving the microduplication of band 11.2 on the short arm of human chromosome 17 (17p11.2). The duplication was first described as a case study in 1996. In 2000, the first study of the disease was released, and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. PTLS is named for two researchers involved in the latter phases, Drs. Lorraine Potocki and James R. Lupski of Baylor College of Medicine.

<span class="mw-page-title-main">Pitt–Hopkins syndrome</span> Medical condition

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DECIPHER is a web-based resource and database of genomic variation data from analysis of patient DNA. It documents submicroscopic chromosome abnormalities and pathogenic sequence variants, from over 25000 patients and maps them to the human genome using Ensembl or UCSC Genome Browser. In addition it catalogues the clinical characteristics from each patient and maintains a database of microdeletion/duplication syndromes, together with links to relevant scientific reports and support groups.

<span class="mw-page-title-main">3q29 microdeletion syndrome</span> Medical condition

3q29 microdeletion syndrome is a rare genetic disorder resulting from the deletion of a segment of chromosome 3. This syndrome was first described in 2005.

1q21.1 deletion syndrome is a rare aberration of chromosome 1. A human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 deletion syndrome, one chromosome of the pair is not complete, because a part of the sequence of the chromosome is missing. One chromosome has the normal length and the other is too short.

<span class="mw-page-title-main">1q21.1 duplication syndrome</span> Medical condition

1q21.1 duplication syndrome, also known as 1q21.1 microduplication, is an uncommon copy number variant associated with several congenital abnormalities, including developmental delay, dysmorphic traits, autism spectrum disorder, and congenital cardiac defects. Common facial features include frontal bossing, hypertelorism, and macrocephaly. Around 18 and 29% of patients with 1q21.1 microduplications have congenital cardiac abnormalities. 1q21.1 duplication syndrome is caused by microduplications of the BP3-BP4 region. 18-50% are de novo deletions and 50-82% inherited from parents. The 1q21.1 area, one of the largest regions in the human genome, is highly susceptible to copy number variation due to its frequent low-copy duplications. Whole exon sequencing and quantitative polymerase chain reaction can provide a precise molecular diagnosis for children with 1q21.1 microduplication syndrome.

<span class="mw-page-title-main">Sotos syndrome</span> Genetic overgrowth disorder

Sotos syndrome is a rare genetic disorder characterized by excessive physical growth during the first years of life. Excessive growth often starts in infancy and continues into the early teen years. The disorder may be accompanied by autism, mild intellectual disability, delayed motor, cognitive, and social development, hypotonia, and speech impairments. Children with Sotos syndrome tend to be large at birth and are often taller, heavier, and have relatively large skulls (macrocephaly) than is normal for their age. Signs of the disorder, which vary among individuals, include a disproportionately large skull with a slightly protrusive forehead, large hands and feet, large mandible, hypertelorism, and downslanting eyes. Clumsiness, an awkward gait, and unusual aggressiveness or irritability may also occur.

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<span class="mw-page-title-main">Microdeletion syndrome</span> Syndrome caused by chromosomal deletion

A microdeletion syndrome is a syndrome caused by a chromosomal deletion smaller than 5 million base pairs spanning several genes that is too small to be detected by conventional cytogenetic methods or high resolution karyotyping. Detection is done by fluorescence in situ hybridization (FISH). Larger chromosomal deletion syndromes are detectable using karyotyping techniques.

Burnside–Butler syndrome is a name that has been applied to the effects of microdeletion of DNA sequences involving four neurodevelopmental genes. Varying developmental and psychiatric disorders have been attributed to the microdeletion; however, the great majority of people with the deletion do not have any clinical features associated with it. More studies are needed to delineate the range of clinical presentation.

<span class="mw-page-title-main">Xp11.2 duplication</span> Genetic disorder

Xp11.2 duplication is a genomic variation marked by the duplication of an X chromosome region on the short arm p at position 11.2, defined by standard karyotyping (G-banding). This gene-rich, rearrangement prone region can be further divided into three loci - Xp11.21, Xp11.22 and Xp11.23. The duplication could involve any combination of these three loci. While the length of the duplication can vary from 0.5Mb to 55 Mb, most duplications measure about 4.5Mb and typically occur in the region of 11.22-11.23. Most affected females show preferential activation of the duplicated X chromosome. Features of affected individuals vary significantly, even among members of the same family. The Xp11.2 duplication can be 'silent' - presenting no obvious symptoms in carriers - which is known from the asymptomatic parents of affected children carrying the duplication. The common symptoms include intellectual disabilities, speech delay and learning difficulties, while in rare cases, children have seizures and a recognizable brain wave pattern when assessed by EEG (electroencephalography).

<span class="mw-page-title-main">DiGeorge syndrome</span> Medical condition caused by chromosomal abnormality

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent infections, developmental disability, intellectual disability and cleft palate. Associated conditions include kidney problems, schizophrenia, hearing loss and autoimmune disorders such as rheumatoid arthritis or Graves' disease.

16p11.2 deletion syndrome is a rare genetic condition caused by microdeletion on the short arm of chromosome 16. Most affected individuals experience global developmental delay and intellectual disability, as well as childhood-onset obesity. 16p11.2 deletion is estimated to account for approximately 1% of autism spectrum disorder cases.

References

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  5. ↑ Nagamani SCS, Erez A, Shen J, Li C, Roeder E, Cox S, Karavati L, Pearson M, Kang SHL, Sahoo T, Lalani SR, Stankiewicz P, Sutton VR, Cheung SW (2010). "Clinical spectrum associated with recurrent genomic rearrangements in chromosome 17q12". European Journal of Human Genetics. 18 (1): 278–284. doi: 10.1038/ejhg.2009.174 . PMC   2987224 . PMID   19844256.
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  10. ↑ Genetics Home Reference. "What is a gene mutation and how do mutations occur?". Medline Plus. Retrieved 22 February 2021.
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  12. ↑ Roehlen N, Hilger H, Stock F, Gläser B, Guhl J, Schmitt-Graeff A, Seufert J, Laubner K (October 2018). "17q12 Deletion Syndrome as a Rare Cause for Diabetes Mellitus Type MODY5". The Journal of Clinical Endocrinology & Metabolism. 103 (10): 3601–3610. doi: 10.1210/jc.2018-00955 . PMID   30032214.
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