Novel fetal phenotype for “FRYL-related neurodevelopmental disorder with multiple anomalies
Prenatal Genetics
-
Primary Categories:
- Prenatal Genetics
-
Secondary Categories:
- Prenatal Genetics
Introduction
Prenatal genetics is an intricate and dynamic realm of medicine. In cases with fetal anomalies, specialized providers in maternal fetal medicine and genetic counseling collaborate to shed light on diagnosis, natural history and prognosis; while providing psychotherapeutic support which allows for familial adjustment and informed decision-making.
Here we report on a fetus with multiple congenital anomalies and whose whole exome sequencing (WES) analysis revealed a pathogenic variant in the FRYL gene. Review of the literature revealed consistency among impacted organs; however, did not include findings present in our patient such as diaphragmatic hernia (CDH) and anophthalmia. In addition, the mortality rate of individuals in the literature was lower than one would have assumed based on the ultrasound findings alone in our case. This case highlights the importance of comprehensive fetal genetic testing, literature analysis, and tailored ultrasound practices for prognostic counseling.
Case Presentation
A 29-year-old G3P1 presented at 28 weeks for second-opinion fetal ultrasound which revealed fetal growth restriction, moderate polyhydramnios, left-sided CDH with cardiac dextroposition, severely shortened long bones in the left forearm (mesomelia), right pelvic kidney, and possible hemivertebrae. Lung to head ratio (LHR) was less than one, predicting poor prognosis for survival.
Diagnostic Workup
SNP-based chromosomal microarray revealed a male fetus with an incidental pathogenic 17q21.31 deletion (BRCA1 gene). Whole exome sequencing revealed a pathogenic frame-shift mutation in the FRYL gene consistent with the autosomal dominant “FRYL-related neurodevelopmental disorder with multiple anomalies”. At 35 weeks’ gestation, the patient presented with PPROM and underwent urgent cesarean section in the setting of non-reassuring fetal heart tones. The infant was intubated and transferred to the NICU. Physical examination revealed left anophthalmia, micrognathia, cryptorchidism and hypospadias. X-rays showed hypoplastic left radius, absent left thumb, multiple vertebral anomalies, left diaphragmatic hernia, and dysplastic left ribs. Postnatal echo identified mild aortic arch hypoplasia, unicuspid aortic valve, and a large PDA. Abdominal ultrasound showed horseshoe kidney.
Treatment and Management
Pediatric surgery required improved ventilation and ability to tolerate conventional ventilator / CPAP prior to operation. Unfortunately, there was minimal improvement in respiratory status and the family ultimately desired compassionate extubation.
Outcome and Follow-Up
The baby passed away at 4 days of life. Parental targeted FRYL variant analyses are pending.
Discussion
To our knowledge, only one major study currently delineates the phenotype associated with pathogenic variants in the FRYL gene. Pan et al., 2024, have documented anomalies including developmental delay/intellectual disability, central nervous system anomalies, psychiatric conditions, dysmorphic features, shortened long bones, cardiovascular, genitourinary, and gastrointestinal anomalies. None of the individuals previously studied had the same variant identified in our study. In addition, clinical findings unique to our case (CDH and anophthalmia, metacarpal anomalies, vertebral/tib anomalies) have not previously been linked with a pathogenic variant in the FRYL gene; although loss of function studies in the Drosophila homologue, FRY, have been shown to disrupt eye development.
Conclusion
FRYL-related neurodevelopmental disorder with multiple anomalies is considered a novel condition without entries in OMIM at this time. The FRYL gene has not previously been associated with CDH and is not included in GeneReviews® or major testing panels related to CDH. Our case supports variable expressivity and mortality associated with those who have pathogenic variants in the FRYL gene. We propose the genetic evaluation for CDH should include more comprehensive testing such as WES, or addition of targeted genes such as FRYL into CDH gene panels. The clinical evaluation of a fetus diagnosed with CDH should expand to include a fetal skeletal survey and evaluation of the fetal orbits.
Prenatal genetics is an intricate and dynamic realm of medicine. In cases with fetal anomalies, specialized providers in maternal fetal medicine and genetic counseling collaborate to shed light on diagnosis, natural history and prognosis; while providing psychotherapeutic support which allows for familial adjustment and informed decision-making.
Here we report on a fetus with multiple congenital anomalies and whose whole exome sequencing (WES) analysis revealed a pathogenic variant in the FRYL gene. Review of the literature revealed consistency among impacted organs; however, did not include findings present in our patient such as diaphragmatic hernia (CDH) and anophthalmia. In addition, the mortality rate of individuals in the literature was lower than one would have assumed based on the ultrasound findings alone in our case. This case highlights the importance of comprehensive fetal genetic testing, literature analysis, and tailored ultrasound practices for prognostic counseling.
Case Presentation
A 29-year-old G3P1 presented at 28 weeks for second-opinion fetal ultrasound which revealed fetal growth restriction, moderate polyhydramnios, left-sided CDH with cardiac dextroposition, severely shortened long bones in the left forearm (mesomelia), right pelvic kidney, and possible hemivertebrae. Lung to head ratio (LHR) was less than one, predicting poor prognosis for survival.
Diagnostic Workup
SNP-based chromosomal microarray revealed a male fetus with an incidental pathogenic 17q21.31 deletion (BRCA1 gene). Whole exome sequencing revealed a pathogenic frame-shift mutation in the FRYL gene consistent with the autosomal dominant “FRYL-related neurodevelopmental disorder with multiple anomalies”. At 35 weeks’ gestation, the patient presented with PPROM and underwent urgent cesarean section in the setting of non-reassuring fetal heart tones. The infant was intubated and transferred to the NICU. Physical examination revealed left anophthalmia, micrognathia, cryptorchidism and hypospadias. X-rays showed hypoplastic left radius, absent left thumb, multiple vertebral anomalies, left diaphragmatic hernia, and dysplastic left ribs. Postnatal echo identified mild aortic arch hypoplasia, unicuspid aortic valve, and a large PDA. Abdominal ultrasound showed horseshoe kidney.
Treatment and Management
Pediatric surgery required improved ventilation and ability to tolerate conventional ventilator / CPAP prior to operation. Unfortunately, there was minimal improvement in respiratory status and the family ultimately desired compassionate extubation.
Outcome and Follow-Up
The baby passed away at 4 days of life. Parental targeted FRYL variant analyses are pending.
Discussion
To our knowledge, only one major study currently delineates the phenotype associated with pathogenic variants in the FRYL gene. Pan et al., 2024, have documented anomalies including developmental delay/intellectual disability, central nervous system anomalies, psychiatric conditions, dysmorphic features, shortened long bones, cardiovascular, genitourinary, and gastrointestinal anomalies. None of the individuals previously studied had the same variant identified in our study. In addition, clinical findings unique to our case (CDH and anophthalmia, metacarpal anomalies, vertebral/tib anomalies) have not previously been linked with a pathogenic variant in the FRYL gene; although loss of function studies in the Drosophila homologue, FRY, have been shown to disrupt eye development.
Conclusion
FRYL-related neurodevelopmental disorder with multiple anomalies is considered a novel condition without entries in OMIM at this time. The FRYL gene has not previously been associated with CDH and is not included in GeneReviews® or major testing panels related to CDH. Our case supports variable expressivity and mortality associated with those who have pathogenic variants in the FRYL gene. We propose the genetic evaluation for CDH should include more comprehensive testing such as WES, or addition of targeted genes such as FRYL into CDH gene panels. The clinical evaluation of a fetus diagnosed with CDH should expand to include a fetal skeletal survey and evaluation of the fetal orbits.
)
)
)
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
)
){kind=logo}
)
)
)
)
)
)
){kind=logo}
){kind=logo}
){kind=logo}