Clinical characteristics.

6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is defined as transient neonatal diabetes mellitus caused by genetic aberrations of the imprinted locus at 6q24. The cardinal features are: severe intrauterine growth restriction, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia may be present. 6q24-TNDM associated with a multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last longer than a year. Although insulin is usually required initially, the need for insulin gradually declines over time. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Diabetes mellitus may recur in adolescence or later in adulthood. Women who have had 6q24-TNDM are at risk for relapse during pregnancy.

Diagnosis/testing.

The diagnosis of 6q24-TNDM is established in a proband with transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the 6q24 differentially methylated region (DMR). 6q24-TNDM is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI). The DMR (i.e., PLAGL1 TSS alt-DMR) is present within the shared promoter of these genes. Normally, expression of the maternal alleles of PLAGL1 and HYMAI is silenced by DMR methylation and only the paternal alleles of PLAGL1 and HYMAI are expressed. Additional molecular genetic testing can establish the underlying genetic mechanism, which is required for genetic counseling. Three different genetic mechanisms resulting in twice the normal dosage of PLAGL1 and HYMAI (and thus causing 6q24-TNDM) are (1) paternal uniparental disomy of chromosome 6, (2) duplication of 6q24 on the paternal allele, and (3) hypomethylation of the maternal PLAGL1 TSS alt-DMR, resulting in inappropriate expression of the maternal PLAGL1 and HYMAI alleles. Maternal PLAGL1 TSS alt-DMR hypomethylation may result from an isolated imprinting variant or as part of MLID. Biallelic ZFP57 pathogenic variants account for almost half of TNDM-MLID.

Management.

Treatment of manifestations: Rehydration and IV insulin are usually required at the time of diagnosis; subcutaneous insulin is introduced as soon as possible and used until blood glucose levels stabilize. Later recurrence of diabetes may require diet modifications alone, oral agents, or insulin.

Prevention of secondary complications: Prompt treatment of dehydration to avoid sequelae.

Surveillance: Periodic glucose tolerance tests (abnormalities suggest future recurrence); monitoring of growth and development.

Agents/circumstances to avoid: Factors that predispose to late-onset diabetes or risk factors for cardiovascular disease.

Evaluation of relatives at risk: Screening for diabetes mellitus in relatives who have inherited a paternal 6q24 duplication or who are at risk of having inherited two ZFP57 pathogenic variants.

Genetic counseling.

The risk to sibs and offspring of a proband of having 6q24-TNDM or of developing diabetes later in life depends on the genetic mechanism in the family. Recurrence risk counseling by a genetics professional is strongly recommended. 6q24-TNDM caused by paternal UPD6 is typically a de novo, non-recurrent event. 6q24-TNDM caused by paternal duplication of 6q24 can occur de novo, be inherited in an autosomal dominant manner, or be inherited as part of a complex chromosome rearrangement; TNDM caused by inherited duplication of 6q24 may recur in sibs and offspring of a proband if the duplication is inherited from the father. Prenatal diagnosis of paternal duplication of 6q24 is possible in pregnancies at risk for a structural chromosome abnormality. TNDM caused by hypomethylation of the PLAGL1 TSS alt-DMR is a de novo non-recurrent event in the majority of individuals, particularly if hypomethylation is restricted to this DMR and does not affect other imprinted loci. However, TNDM as part of a multilocus imprinting disturbance (TNDM-MLID) has a significant genetic component. TNDM-MLID is inherited in an autosomal recessive manner when caused by pathogenic variants in ZFP57; however, the phenotype of homozygous or compound heterozygous sibs is variable and cannot be predicted by molecular genetic testing. Pathogenic variants in additional genes are suspected of causing TNDM-MLID but are currently unknown. Therefore, caution should be exercised when counseling the heritability of TNDM associated with imprinting disturbance at the PLAGL1 TSS alt-DMR.

Suggestive Findings

Diagnosis of 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) should be suspected in individuals with the following clinical features:

• Severe intrauterine growth restriction
• Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following:
  • Hyperglycemia
  • Dehydration
  • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations
  • Absence of ketoacidosis. Ketones are usually not present in the urine.
  • Absence of islet cell antibodies
  • Presence of a pancreas

Establishing the Diagnosis

The diagnosis of 6q24-TNDM is established in a proband with one of the following:

• Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the PLAGL1 TSS alt-DMR, through one of the following mechanisms:
  • Partial or complete paternal uniparental disomy of chromosome 6
  • Paternal duplication of 6q24
  • Hypomethylation of the maternal PLAGL1 TSS alt-DMR
• Biallelic pathogenic (or likely pathogenic) variants in ZFP57 identified on molecular genetic testing
  Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ZFP57 variants of uncertain significance (or of one known ZFP57 pathogenic variant and one ZFP57 variant of uncertain significance) does not establish or rule out the diagnosis.

The maternal alleles of PLAGL1 and HYMAI are silenced by methylation of the PLAGL1 TSS alt-DMR, and only the paternal alleles of PLAGL1 and HYMAI are expressed. In 6q24-TNDM, PLAGL1 and HYMAI alleles are overexpressed through one of three genetic mechanisms (see Figure 1):

Figure 1.

Three different genetic mechanisms cause 6q24-TNDM: paternal uniparental disomy of chromosome 6 (UPD6) (41%); duplication of 6q24 on the paternal allele (29%); and hypomethylation of the maternally inherited PLAGL1 TSS alt-DMR (30%). Hypomethylation of (more...)

• Hypomethylation of the PLAGL1 TSS alt-DMR, either:
  • As an isolated imprinting defect of the PLAGL1 TSS alt-DMR; or
  • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in ZFP57 or by as-yet-unknown mechanisms.
• Partial or complete paternal uniparental disomy of chromosome 6 (UPD6) that includes the PLAGL1 and HYMAI loci
• Paternal duplication of 6q24. Usually a submicroscopic duplication results in the presence of two copies of PLAGL1 and HYMAI on one paternal chromosome 6.
  Note: In individuals with 6q24 duplication of the paternal allele, the presence of two unmethylated alleles and one methylated allele of the PLAGL1 TSS alt-DMR causes apparent partial hypomethylation of the PLAGL1 TSS alt-DMR.

Molecular genetic testing approaches can include DNA methylation studies, chromosomal microarray analysis (CMA), uniparental disomy studies, targeted duplication analysis, and single-gene testing.

Clinical Description

Intrauterine growth restriction may be noted in the third trimester. The mean birth weight in a study of 30 infants was 1,930 g at 39 weeks' gestation [Temple et al 2000]; this finding is in keeping with other studies [Metz et al 2002, Diatloff-Zito et al 2007]. Because the plasma concentration of insulin is low at the time of diagnosis, it is assumed that low birth weight is a result of low in utero levels of insulin, an important prenatal growth factor.

Diabetes mellitus tends to develop in the first week of life, although it may not be recognized until later. Hyperglycemia may be identified by chance during routine investigations in the newborn period for a sick dehydrated infant. Infants rapidly become dehydrated and usually require insulin. The diabetes may be resistant to treatment initially. Occasionally insulin is not required and neonates are treated with rehydration alone.

Diabetes mellitus lasts on average three months but has been reported to last longer than a year [Temple et al 2000]. The need for insulin gradually declines. This is often accompanied by a significant weight gain and catch-up growth, and some infants become overweight in the first year [Metz et al 2002].

Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Few studies have been performed during this period and so the extent of these episodes is not known. Shield et al [2004] studied seven children during this period and found low insulin secretion in four and normal insulin secretion in three.

Diabetes may recur in very early childhood. The average age of recurrence in the series of Temple et al [2000] was 14 years, coinciding with puberty. Some individuals require insulin; others are treated with oral drugs or diet alone. In a series from France, five of seven individuals developed diabetes again after age eight years [Metz et al 2002].

Women are at risk for relapse during pregnancy and may present with gestational diabetes mellitus.

Permanent diabetes mellitus can occur in up to 50% in some series [Temple et al 2000], although this figure may overestimate the actual risk because of the bias of identifying affected individuals. There is usually some residual endogenous insulin production; however, insulin therapy may be needed.

Studies have not been performed to assess the level of diabetes-related complications that can occur in this disorder. One individual with poor compliance with treatment had persistent hyperglycemia from ages 14 to 28 years. He did not develop ketoacidosis but did develop evidence of microangiopathy [Valerio et al 2004].

Other. Macroglossia and umbilical hernia are sometimes observed. No other dysmorphic features are consistently associated with this condition. Screening for congenital hypothyroidism is prudent.

6q24-TNDM caused by generalized multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations.

Intelligence and growth are usually normal in this condition except in individuals with loss of methylation at multiple loci, who may have developmental delay. However, the long-term outcomes for most individuals are still not known.

Genotype-Phenotype Correlations

Diabetes mellitus. No difference in the severity, duration, or relapse rate of diabetes has been detected between the 6q24-TNDM etiologic subgroups [Temple et al 2000].

Non-diabetes manifestations vary by causative genetic mechanism. Congenital anomalies were significantly more frequent in individuals with paternal uniparental disomy of chromosome 6 (UPD6) or MLID than in those with 6q24 duplication or isolated hypomethylation defects [Docherty et al 2013].

• UPD6. The majority of UPD6 is isodisomic; i.e., two copies of chromosome 6 are identical and therefore the affected individual is at increased risk for rare autosomal recessive disorders that may be unmasked by this unusual inheritance pattern. The most common is HFE-associated hereditary hemochromatosis, for which testing can be performed in adulthood. Methylmalonic acidemia and congenital adrenal hyperplasia caused by 21-hydroxylase deficiency have also been described as occurring through this mechanism.
• 6q duplication. Cytogenetically visible duplication of 6q can also be associated with learning difficulties related to other genes within the duplicated region. Note: Individuals with a submicroscopic 6q24 duplication are usually of normal intelligence.
• Hypomethylation of the maternal PLAGL1 TSS alt-DMR. An imprinted differentially methylated region overlaps an alternative transcriptional start-site of PLAGL1, and hypomethylation of this PLAGL1 TSS-alt DMR is associated with TNDM. Non-diabetes manifestations are more likely in the subgroup with a more generalized hypomethylation at imprinted loci (i.e., MLID) and can include significant learning difficulties [Boonen et al 2008, Mackay et al 2008]. No correlation has been observed between clinical severity and either the degree of hypomethylation or the range of loci involved. For example, the features seen in individuals with 6q24-TNDM caused by homozygous or compound heterozygous ZFP57 pathogenic variants can vary from severe intellectual disability and early infant death to a normal phenotype. It is therefore difficult to predict the phenotype in individuals with MLID, possibly because of the inability to interrogate all imprinted loci.

Penetrance

Reduced penetrance of the 6q24-TNDM has rarely been described, but has been noted in sibs of affected individuals. The sibs reported did not have a history of neonatal diabetes mellitus but were found to have either a paternal duplication of 6q24 or biallelic ZFP57 pathogenic variants [Valerio et al 2004, Boonen et al 2013].

Prevalence

The incidence of neonatal diabetes is reported to be 1:215,000 to 1:400,000 [Polak & Shield 2004, Stanik et al 2007, Wiedemann et al 2010]; 50% of neonatal diabetes mellitus is transient rather than permanent (see Permanent Neonatal Diabetes Mellitus).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with 6q24-related transient neonatal diabetes mellitus (6q24-TNDM), the following evaluations are recommended if they have not already been completed:

• Birth weight, length, and head circumference and any subsequent growth parameters
• General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus
• Neurologic examination and developmental assessment
• Investigation of the anatomy of the pancreas by ultrasound examination or MRI
• Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by ZFP57 pathogenic variants
• Brain MRI examination if evidence of developmental delay or hypotonia
• Serum glucose concentration
• C peptide measurement
• Pancreatic beta cell autoantibody measurements
• Liver function and thyroid function tests
• Consultation with a pediatric endocrinologist for follow up of diabetes
• Consultation with a clinical geneticist and/or genetic counselor

Individuals with multilocus imprinting disturbance (MLID) should be evaluated for hypotonia and other neurologic features including epilepsy, congenital heart disease, deafness, renal malformations, and pseudohypoparathyroidism with measurement of serum concentrations of calcium and phosphate and parathyroid hormone testing.

Treatment of Manifestations

Rehydration and IV insulin on a sliding scale are usually required. Some infants produce some insulin and can be treated by rehydration alone.

Subcutaneous injection of insulin is introduced as soon as possible, often within two weeks. Continuous insulin pump therapy (as opposed to intermittent insulin injections) has been used successfully in a number of cases in the UK and France [JP Shield, personal communication]. Successful treatment with subcutaneous insulin glargine has also been reported [Barone et al 2011].

Blood glucose concentration should be monitored and insulin doses changed accordingly as in the standard treatment for diabetes mellitus. Insulin can be discontinued when blood glucose concentrations stabilize.

Once diabetes mellitus is in remission, parents need to be alerted to the possibility of recurrence of the diabetes mellitus, particularly during periods of illness. Symptoms such as excessive thirst, polyuria, and repeated bacterial infections should prompt measurement of blood glucose concentration.

If diabetes mellitus recurs, treatment may require diet alone, oral agents, or insulin, although the doses of insulin needed tend to be less than those required in type 1 diabetes mellitus (i.e., some residual endogenous insulin remains). It should be noted that insulin is not always required even in the neonatal period. In several individuals, sulphonylureas or diet alone was adequate to treat relapses [Valerio et al 2004].

Note: Macroglossia could potentially cause airway obstruction; macroglossia severe enough to require treatment has not been reported.

Prevention of Secondary Complications

The main concerns are related to failure to make the diagnosis soon enough. Dehydration secondary to hyperglycemia can cause serious long-term sequelae if not treated promptly. Therefore, rehydration is most important in the early stages of the disease.

Surveillance

Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes mellitus in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state. Insulin response to intravenous glucose loading is often normal but suggests future recurrence if abnormal [Shield et al 2004].

Measure growth (height, weight, head circumference) at regular intervals (i.e., at least every 6 months).

Developmental assessment to identify any special educational needs is appropriate.

Children with MLID need to be monitored for developmental delay and special educational needs.

Agents/Circumstances to Avoid

General factors that predispose to late-onset diabetes (e.g., excessive weight gain) or risk factors for cardiovascular disorders should be avoided.

Evaluation of Relatives at Risk

It is appropriate to test apparently asymptomatic at-risk relatives for the 6q24-TNDM genetic mechanism identified in the proband in order to identify family members who would benefit from follow up. (Hyperglycemia may be asymptomatic.)

Recommendations for follow up vary by underlying genetic mechanism:

• 6q24 duplication. Individuals with a 6q24 duplication may not present with diabetes as neonates. However, such individuals are at risk of developing diabetes later in life. Knowing this risk may facilitate prompt evaluation and treatment if they develop symptoms of diabetes. These individuals can also be counseled regarding risks to their offspring. Screening for diabetes mellitus is appropriate for those infants who have inherited the paternal 6q24 duplication.
• Biallelic ZFP57 pathogenic variants. Sibs who inherit biallelic variants are at risk for the same condition (although the clinical findings can be variable) and should undergo screening for diabetes mellitus.
• Hypomethylation at PLAGL1 TSS alt-DMR. Although individuals with 6q24-TNDM as the result of hypomethylation at PLAGL1 TSS alt-DMR generally represent simplex cases (i.e., a single occurrence in a family), it is not clear if all cases are de novo, and there have been relatively few families reported in the literature to determine recurrence risk (see also Genetic Counseling).Screening the mother and sibs of these individuals for hypomethylation may therefore be appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no specific guidelines on pregnancy management for women with a history of 6q24-TNDM. However, it is important to inform health professionals during the pregnancy of a susceptibility to diabetes. Rarely, some affected women with classic 6q24-TNDM genetic aberrations (e.g., duplication of 6q24, paternal uniparental disomy of chromosome 6, methylation defects) will develop gestational diabetes; therefore, pregnancy is thought to be a risk factor for recurrence of diabetes.

If prenatal diagnosis identifies an affected fetus, fetal growth is anticipated to lag during the third trimester.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

6q24-related transient neonatal diabetes mellitus (6q24-TNDM) results from overexpression of imprinted genes at 6q24 (PLAGL1 and HYMAI). Three different genetic mechanisms cause 6q24-TNDM:

• Paternal uniparental disomy of chromosome 6 (41%)
  Both complete and partial paternal uniparental disomy of chromosome 6 are typically de novo events.
• Duplication of 6q24 on the paternal allele (29%)
  Paternal duplication of 6q24 can occur de novo or be inherited. Occasionally, the duplication arises as part of a complex chromosomal rearrangement in a parent.
• Hypomethylation of the maternal PLAGL1 TSS alt-DMR, resulting in loss of the imprinted marking that typically silences the maternal region (30%)
  Maternal PLAGL1 TSS alt-DMR hypomethylation can result from an imprinting defect of the promoter PLAGL1 TSS alt-DMR (isolated) or as part of a generalized multilocus imprinting disturbance (MLID); biallelic (homozygous or compound heterozygous) ZFP57 pathogenic variants account for almost half of TNDM-MLID.

Paternal Uniparental Disomy of Chromosome 6 – Risk to Family Members

Parents, sibs, and offspring of a proband

• Karyotype testing of a proband with paternal uniparental disomy of chromosome 6 (UPD6) is recommended for more accurate determination of recurrence risk.
• The risk to parents, sibs, and offspring of a proband with 6q24-TNDM caused by paternal UPD6 and a normal karyotype is unlikely to be higher than the risk to the general population, as paternal UPD6 is a de novo, typically non-recurrent event.
• If the proband has a chromosome abnormality in addition to paternal UPD6, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.

Paternal Inherited/Derived Duplication of 6q24 (usually submicroscopic tandem duplication) – Risk to Family Members

Parents of a proband

• The father of a proband may have the (submicroscopic or visible) 6q24 duplication identified in the proband and may be at risk of developing diabetes mellitus later in life (or having had a history of early diabetes mellitus) if the 6q24 duplication was inherited from his father.
• Alternatively, the 6q24 duplication may be a de novo occurrence in the proband.
• Recommendations for the evaluation of the father of a proband with 6q24-TNDM include routine cytogenetic analysis and molecular genetic testing to identify a 6q24 duplication if present, and to exclude a balanced/unbalanced translocation involving the 6q24 critical region.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the father:

• If the father does not have a duplication of 6q24, the risk to the sibs depends on the possibility of germline mosaicism in the father (estimated risk: ~1%).
• If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of reduced penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but they are at increased risk of developing diabetes mellitus later in life.
• If the father has a complex chromosomal rearrangement involving 6q24, the risk to sibs is related to the specific rearrangement.

Offspring of a male proband. Each child of a male with 6q24-TNDM caused by duplication of 6q24 has a 50% chance of inheriting the duplication and is at high risk of developing 6q24-TNDM and/or diabetes mellitus later in life.

Offspring of a female proband. Each child of a female with 6q24-TNDM caused by duplication of 6q24 has a 50% chance of inheriting the duplication but is not at increased risk of developing 6q24-TNDM or diabetes mellitus later in life.

Other family members. The risk to more distant family members depends on the status of the proband's parents. Family members may be at risk if the proband has an inherited duplication of 6q24.

Hypomethylation of the Maternal PLAGL1 TSS alt-DMR – Risk to Family Members

Risks depend on the underlying cause of the hypomethylation.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Consideration of prenatal testing for 6q24-TNDM depends on the genetic mechanism in the family: paternal UPD6 is typically a de novo, non-recurrent event; 6q24 duplication may recur when the duplication is inherited from the father; and hypomethylation at imprinted loci caused by biallelic ZFP57 pathogenic variants is inherited in an autosomal recessive manner. Counseling by a genetics professional is strongly recommended.

Prenatal testing and preimplantation genetic testing for pregnancies at risk for:

• Paternal duplication of 6q24 requires prior identification of the structural chromosome abnormality in the family.
• Hypomethylation of the maternal PLAGL1 TSS alt-DMR as a result of biallelic ZFP57 pathogenic variants requires prior identification of the ZFP57 pathogenic variants in the family. However, the phenotype associated with biallelic ZFP57 pathogenic variants is variable and cannot be accurately predicted by the results of prenatal molecular genetic testing.

Molecular Pathogenesis

The molecular pathogenesis of 6q24-TNDM is not yet understood. The minimal disease-associated region has been refined [Docherty et al 2010] excluding all but PLAGL1 and HYMAI as candidate genes for 6q24-TNDM. Maternal alleles are methylated within the differentially methylated region (DMR; imprinting center) of PLAGL1 (ZAC) and HYMAI, thereby silencing their expression. Paternal alleles are not methylated and are expressed. Disease occurs through either loss of the methylation imprint that silences the maternal allele or a rearrangement that results in duplication and overexpression of the paternal allele. See Establishing the Diagnosis for genetic mechanisms.

All 6q24-TNDM mechanisms described result in overexpression of PLAGL1. In most human fetal tissues, PLAGL1 is paternally expressed due to lack of paternal methylation within the DMR [Varrault et al 2001]. No enhancers or insulators of the region have been identified. In adult tissues, paternal expression is restricted to a minority of tissues such as skin fibroblasts. Biallelic expression results from an alternative non-imprinted promoter, 55 kb upstream of the imprinted promoter [Valleley et al 2007]. Many PLAGL1 transcript variants differing in the 5' UTR and encoding two different isoforms are known for this gene.

The mechanism whereby PLAGL1 overexpression causes transient early diabetes mellitus is not fully understood. PLAGL1 codes for a zinc finger protein and overexpression causes cell cycle arrest and apoptosis in cell lines; PLAGL1 regulates the pituitary adenylate cyclase-activating polypeptide receptor (PACAP1), which stimulates insulin secretion. Downstream targets of PLAGL1 are not fully characterized, although Arima et al [2005] showed that PLAGL1 binds to the CpG island in KCNQ1OT1, which negatively regulates CDKN1C. Varrault et al [2006] showed that PLAGL1 is an important member of a cellular network of imprinted genes involved in fetal growth.

A mouse model for TNDM [Ma et al 2004] demonstrated impaired glucose homeostasis in mice with overexpression of plagl1 and showed a downregulation of pdx-1, a key transcription factor vital for normal pancreatic development. Although beta cell mass was reduced in fetal mice, it had recovered by the time of birth; nonetheless, insulin response to hyperglycemia was decreased. It is hypothesized that the beta cell mass is not sufficient to respond during times of excessive physiologic stress, resulting in "breakthrough" diabetes with intercurrent illnesses and sometimes with increasing age.

In keeping with this hypothesis, Valerio et al [2004] have demonstrated in 6q24-TNDM a specific defect of insulin secretion after glucose stimulation. Furthermore, insulin secretion is possible through the stimulatory G protein pathway.

At the molecular level, the picture is complicated by paternally expressed HYMAI, which overlaps PLAGL1 and the 6q24-TNDM DMR. HYMAI lacks an open reading frame and is not translated. It may regulate PLAGL1 expression; its relationship to PLAGL1 and 6q24-TNDM is not yet known.

In fibroblasts from an individual with transient neonatal diabetes mellitus, the monoallelic expression of both PLAGL1 and HYMAI was relaxed, providing strong supportive evidence that the presence of two unmethylated alleles of this locus is indeed associated with the inappropriate expression of neighboring genes [Mackay et al 2002]. The PLAGL1 promoter is localized to the CpG island harboring the methylation imprint associated with 6q24-TNDM, and methylation of this promoter silences its activity [Varrault et al 2001].

ZFP57

Gene structure. The transcript NM_001109809.2 has four coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. ZFP57 missense, nonsense, and frameshift pathogenic variants have been identified [Mackay et al 2008].

Normal gene product. The protein product (ZFP57; NP_001103279.2) of ZFP57 has 53 amino acid residues. It is a Kruppel-associated box (KRAB)-containing protein with seven zinc fingers that functions as a transcriptional regulator.

Abnormal gene product. Biallelic pathogenic ZFP57 variants result in inactivation of ZFP57, a protein important in maintaining genomic imprinting at the DMR of PLAGL1 and HYMAI.

Acknowledgments

IKT and DJGM are supported by Diabetes UK and MRC for work on 6q24 transient neonatal diabetes.

Author History

Louise E Docherty, BSc (hons), PhD; Salisbury NHS Foundation Trust (2012-2018)
Deborah JG Mackay, MA, PhD (2010-present)
Isabel K Temple, MD, MBChB, FRCP (2005-present)

Revision History

• 13 September 2018 (sw) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 27 September 2012 (me) Comprehensive update posted live
• 23 December 2010 (cd) Revision: sequence analysis of ZFP57 available clinically on a limited basis
• 4 February 2010 (me) Comprehensive update posted live
• 10 October 2005 (me) Review posted live
• 10 February 2005 (ikt) Original submission

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