Phenotype to Genotype: A Novel Case Presentation of CPT2 Deficiency Syndrome

Abstract

Prenatal detection of recurrent structural anomalies presents complex challenges in fetal prognosis and genetic counseling. We report the case of a 25-year-old woman with three consecutive pregnancies affected by bilateral hyperechoic, enlarged fetal kidneys and associated anomalies. In the first pregnancy, anomaly scan at 18 + 6 weeks revealed enlarged hyperechoic kidneys, Dandy-Walker malformation, and echogenic bowel. The pregnancy was terminated; microarray analysis was normal. A year later, her second pregnancy showed similar renal findings along with enlarged lateral ventricles, absent cavum septum pellucidum, and microcephaly. Trio whole-exome sequencing identified compound heterozygous variants in the CPT2 gene in the fetus: c.28_29insAGCAAG and c.1891C > T. Both parents were found to be heterozygous carriers. In the third pregnancy, clinical exome sequencing was offered as prenatal testing despite a normal ultrasound. The fetus was initially reported as “affected” with the same compound heterozygous CPT2 variants. However, reanalysis by a clinical geneticist revealed that both variants were in cis configuration in the parents and fetus, indicating a carrier status rather than disease. This case underscores the importance of detailed variant interpretation, phase determination, and expert genetic counseling in managing suspected fetal CPT2 deficiency, especially in cases presenting with recurrent antenatal anomalies.

 

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Keywords

CPT2 gene - fetal renal anomalies - prenatal diagnosis - compound heterozygosity - genetic counseling

Introduction

In today's era, it has become increasingly challenging for practicing obstetricians to counsel regarding the prognosis of a fetus with structural abnormalities, detected prenatally at the time of an anomaly scan. The finding of enlarged hyperechogenic fetal kidneys during pregnancy is one such anomaly that, when identified early, requires health care professionals to provide appropriate medical guidance and management for the expectant parents.

If the renal parenchyma of the fetal kidneys is more echogenic than the fetal liver, they are considered to be hyperechogenic.[1] It becomes more apparent with associated loss of corticomedullary differentiation. As there are various etiologies associated with it, the outcomes also become variable. Whether the etiology is obstructive, metabolic, genetic, or transient, it may be one of the first indicators of an underlying disease, and further evaluation becomes imperative. The incidence of hyperechogenic kidneys is reported as 1.6 per 1,000 scans,[2] with congenital abnormalities of the kidneys and the genitourinary tract (CAKUT) representing 15 to 20% of all prenatally diagnosed congenital anomalies. Hence, evaluation of hyperechogenic kidneys for an etiological diagnosis is important for appropriate genetic counseling.

The differentials vary with findings related to kidney size, corticomedullary differentiation, renal pelvis dilatation, presence of renal cysts, quantity of amniotic fluid and whether it is isolated as in cases of autosomal dominant or autosomal recessive polycystic kidney disease (ADPCKD/ARPCKD), or nonisolated as in overgrowth syndromes like Beckwith–Weidemann syndrome or an aneuploidy. It may even be associated with fetal infections.[3] [4] This makes both evaluation and counseling intensive.

 

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Case

Our case study reports a 25-year-old primigravida who presented to us at 18 weeks 6 days at the Department of Fetal Medicine, Apollo Hospitals, Amritsar, Punjab, India, for a detailed anomaly scan. She did not have any medical conditions or any specific family history. They were a nonconsanguineous couple. Findings were suggestive of bilateral hyperechogenic and enlarged kidneys ([Fig. 1A]). Associated anomalies were enlarged cerebral ventricles ([Fig. 1B]) with an enlarged cisterna magna and a hypoplastic cerebellum suggestive of Dandy–Walker malformation ([Fig. 1C]). Invasive testing was offered; however, the pregnancy was discontinued as per the couple's wish. Microarray (CMA 315 K) testing was performed on the products of conception (POC). The report was normal and not suggestive of microdeletions or microduplications. The patient came for follow-up in a subsequent pregnancy 1 year later. The nuchal translucency scan was normal and low risk for aneuploidies. A follow-up early anomaly scan was done at 16 weeks. Findings were suggestive of a subchorionic collection measuring 3.7 × 0.8 cm with echogenic bowel with slightly prominent looking kidneys (left kidney measuring 10 mm in length, 8 mm in width, and 7 mm in anteroposterior diameter and the right kidney measuring 11 mm in length, 8 mm in width, and 6 mm in anteroposterior diameter) of normal echogenicity and no other associated gross structural anomalies. Invasive testing was offered, but the couple wanted to wait for a follow-up detailed anomaly scan at 20 weeks. This revealed bilateral enlarged hyperechogenic kidneys ([Fig. 2A, B]). Additional findings of prominent bilateral cerebral ventricles (left ventricle measuring 8 mm and right ventricle measuring 9 mm) with absent cavum septum pellucidum were present. The fetal head circumference was below the 3rd centile for gestation, suggesting microcephaly. Bowel appeared echogenic. The family was counseled, and they opted to discontinue the pregnancy. Trio whole-exome sequencing (WES) was performed on the couple and the POC.

Fig. 1 (A) Bilateral hyperechogenic and enlarged kidneys. (B) Enlarged bilateral ventricles. (C) Enlarged cisterna magna and a hypoplastic cerebellum suggestive of Dandy–Walker malformation.

Fig. 2 (A, B) Bilateral enlarged and hyperechogenic kidneys in coronal view and sagittal view.

Results of WES in the couple suggested a heterozygous c.28_29insAGCAAG (p.Trp10delinsTerGlnGly) and c.1891C > T (p.Arg631Cys) variant in the CPT2 gene, present in both husband and wife, which meant two variants of the CPT2 gene were present in the couple ([Table 1]).

Table 1 Segregation of CPT 2 variants in the couple and fetus with pathogenic classification

Gene	Location	Variant	Mother	Father	Fetus 1	Current fetus	Disease (inheritance)	Classification
CPT 2	Chr1:53662643T > TAGCAAG Exon 1NM_000098.3	c.28_29insAGCAAG(p.Trp10delinsTerGlnGly)	Heterozygous	Heterozygous	Homozygous	Heterozygous	CPT2 deficiency infantile/CPT2 deficiency lethal neonatal	Pathogenic
CPT 2	Chr1:53679181C > T Exon 5NM_000098.3	c.1891C > T(p.Arg631Cys)	Heterozygous	Heterozygous	Homozygous	Heterozygous	CPT2 deficiency infantile/CPT2 deficiency lethal neonatal	Pathogenic

Note: Couple and current fetus whole exome sequencing report suggesting heterozygous c.28_29insAGCAAG (p.Trp10delinsTerGlnGly) and c.1891C > T (p.Arg631Cys) variant in the CPT2 gene. Fetus 1 is homozygous for both variants.

Samples of the fetus (second pregnancy) showed a homozygous c.28_29insAGCAAG (p.Trp10delinsTer) and a homozygous c.1891C > T (p.Arg631Cys) variant in the CPT2 gene, which meant four variants of the CPT2 gene were present in the fetus ([Table 1]). No significant maternal cell contamination was detected on polymerase chain reaction-based variable number tandem repeat analysis with a lower limit of detection of 10%.

A year later, in her third conception, knowing their genetic carrier status, clinical exome sequencing was offered as an invasive antenatal diagnostic test. The couple were counselled regarding the options of chorionic villous sampling at the time of her nuchal translucency scan (which indicated a structurally normal-looking fetus), for earlier diagnosis. However, they chose to wait until the early anomaly scan. The ultrasound findings were normal, and pretest counseling was done before the amniocentesis was performed.

The report by the genetic laboratory suggested once again an affected fetus with compound heterozygosity. The fetus showed two variants in the CPT2 gene: c.28_29insAGCAAG (p.Trp10delinsTerGlnGly) and c.1891C > T (p.Arg631Cys) variant. This was interpreted by the laboratory as a compound heterozygote for the CPT2 gene and was reported as “affected.”

Compound heterozygosity suggests that the mutations occur on different copies of the gene, in turn completely knocking out the gene function. However, this was completely unexpected as in the current (third) pregnancy, the ultrasound was normal with no renal or cranial anomalies as seen in her previous pregnancy. A consultation of the couple was scheduled with the clinical geneticist and the genetic reports and data were reanalysed.

A reanalysis of the genetic data by the clinical geneticist was done. As the parental segregation was already known from the trio exome sequencing done posttermination of the second pregnancy, the phase of the two variants was already identified in the CPT2 gene. The couple was explained that both the variants were present on one allele (cis form) in the parents, making them carriers and not affected by carnitine palmitoyltransferase deficiency ([Fig. 3]). Similarly, in the fetus, both variants were present on the same allele as the parents ([Table 1]). A neurosonogram was subsequently done for the fetus in the current pregnancy (third) to reconfirm that there were no cranial anomalies in the fetus.

Fig. 3 Both the variants were present on one allele (cis form) in the parents, hence they were carriers and not affected.

It was thus proclaimed that the fetus, too, was a carrier like the parents, unaffected. The couple was reassured on these lines, and the third pregnancy was continued to term to deliver a healthy baby girl weighing 2,600 g.

 

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Discussion

Hyperechogenic kidneys are associated with renal disease in up to 94% of cases; however, in isolated cases with normal amniotic fluid, it may represent a normal variant. In our case, associated findings were noted in both affected pregnancies. Though the microarray was normal in the first pregnancy, WES of the POC in the second pregnancy was suggestive of homozygous variants of both pathogenic and likely pathogenic mutations of the CPT2 gene, similar to the WES of parents (who were of carrier status) also tested at the same time.

CPT2 (carnitine palmitoyltransferase) muscle deficiency is the most common form of muscle fatty acid metabolism disorders.[5] Carnitine palmitoyltransferase 2 deficiency due to mutations in the CPT2 gene is often diagnosed in the postnatal period after more than one terminated pregnancy for multiple malformations and in successive stillbirth or perinatal loss cases.[6] Carnitine palmitoyltransferase 2 (CPT2) deficiency, the most common autosomal recessive inherited disease of the mitochondrial long-chain fatty acid β-oxidation, may result in three distinct clinical phenotypes[7] [8]: a mild adult muscular form which is the most frequent one and is characterized by recurrent episodes of rhabdomyolysis triggered by prolonged exercise, fasting, or febrile illness.[9] A severe infantile hepatocardiomuscular disease[10] which is associated with hypoglycemia, liver failure, cardiomyopathy, and peripheral myopathy and finally, the neonatal form of the disease[11] including dysmorphic features, cystic renal dysplasia, and neuronal migration defects, in addition to symptoms observed in the infantile form. Both the latter forms are life-threatening diseases, and prenatal diagnosis should be offered to couples for a one-fourth risk of having an affected child[12] as these disorders are inherited in an autosomal recessive manner, with a recurrence risk of 25%.

Rarely, presentation is antenatal with cerebral periventricular cysts and cystic dysplastic kidneys.[13]

Diagnosis is usually achieved using either ultrasound detection of renal and brain damage[14] or direct molecular analysis when the disease-causing mutation has been identified in the index patient.[15]

Likewise, in our case, the suspicion of a genetic etiology arose in her second pregnancy when recurrent cranial and renal abnormalities were noted on her scan, and follow-up molecular testing was diagnostic for the mutation in the CPT2 gene.

Genetic counseling is extremely important to evaluate, manage, and prognosticate such cases. Carrier status clarification, along with a detailed family history, helps assess and identify possible patterns that might indicate a higher risk, rather than just a 25% risk, as seen in autosomal recessive disorders.

Literature also states that despite a recessive mode of inheritance, heterozygote carriers could not only be regarded as asymptomatic carriers but may occasionally show mild symptoms later on in adult life.[16] These symptoms may present as recurrent attacks of fatigue, muscle pain, and muscle weakness triggered by prolonged exercise.[17] Some may have only a few episodes of these attacks and remain asymptomatic for most of their lives,[18] while others may experience frequent myalgia even after routine daily activities.[19] In our case, however, the couple experienced no such symptoms.

Therefore, genetic counselling not only offers insight into the above-mentioned issues but also emphasizes the pertinence of prenatal genetic molecular testing. Posttest counseling thereafter is not only technically informative but also an emotional support for managing anxiety and offering coping strategies to the couple, whether it involves dealing with a normal report or managing an affected child.

This case sets a perfect example of how the correct interpretation of reports must be prenatal and documented prior to fetal testing in subsequent pregnancies, so that the couple can be reassured to continue the pregnancy and to finally deliver a healthy child.

 

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Conclusion

In genetically complex scenarios such as CPT2 deficiency, the collaboration of obstetricians, fetal medicine specialists, and clinical geneticists brings a complementary set of skills and expertise that, when combined, contribute to comprehensive care for both the mother and fetus.

 

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Conflict of Interest

None declared.

• References

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Publication History

Article published online:
03 October 2025