Last updated:
1/19/2024
Years published: 2024
NORD gratefully acknowledges Madelyn Gillentine, PhD, Lab Variant Scientist, Molecular Lab, Seattle Children’s Hospital, and Vice President of the HNRNP Family Foundation, for the preparation of this report.
SYNCRIP-related neurodevelopmental disorder (SYNCRIP-RNDD) is a rare disorder characterized by developmental delay/intellectual disability, autism spectrum disorder, motor speech delay and low muscle tone (hypotonia). This condition is caused by changes (variants) in the SYNCRIP gene which is also known as the HNRNPQ gene.
SYNCRIP-RNDD is characterized by developmental delay/intellectual disability, motor and speech delay, hypotonia and behavioral differences. Cognitive disabilities are typically in the mild to borderline intellectual disability range. Autism spectrum disorder is common. Some structural brain anomalies have been observed but are not consistent. Some affected individuals have had seizures and physical differences have been reported in some patients.
global developmental delay/intellectual disability: 92%
speech delay: 77%
autism spectrum disorder: 60%
facial differences: 50%
motor delay: 48%
hypotonia: 43%
vision anomalies: 42%
brain imaging anomalies: 40%
seizures: 33%
movement abnormalities: 32%
hand and feet abnormalities: 29%
genitourinary abnormalities: 24%
growth delay, primarily manifesting as short stature: 22%
Developmental delay/intellectual disability
Most affected individuals that have been described in the medical literature with sufficient clinical information have been described to have borderline to mild developmental delay and/or intellectual disability. Almost 80% have delayed speech and language development, including individuals who are nonverbal or who have trouble speaking (verbal apraxia). For patients with available information, the average age of first words was approximately two years. Mild motor delay has been reported in almost half of individuals, with the average age of first steps being approximately 17 months.
Autism spectrum disorder and other behavioral differences
Behavioral differences are present in about 70% of individuals reported in the medical literature. The most prevalent of these is autism spectrum disorder or autistic features. A smaller group have attention-deficit/hyperactivity disorder (ADHD) or aggressive behaviors. Anxiety and sleep disturbances have also been reported.
Facial and physical features
Most of the facial and physical differences reported are non-specific. About 15% of individuals have a large head (macrocephaly). Hand and feet anomalies, including 2-3 toe webbing (syndactyly), a gap between the great toe and second toe (sandal gap), elongated fingers and flat feet (pes planus) occur in almost 30% of individuals. While facial features vary, a fold of skin from the upper to lower eyelid (epicanthus), abnormalities of the space between the open eyelids (palpebral fissures), large and/or low-set ears and a thin upper lip are the most consistent. Heart (cardiac) issues have not been reported in individuals with SYNCRIP-RNDD.
Hypotonia
Generalized muscle weakness (hypotonia) is seen in 43% of individuals. Two individuals have been reported with spastic muscles.
Vision anomalies
Vision anomalies observed include crossed eyes (strabismus) in 30% of individuals, nearsightedness (myopia) in three individuals, farsightedness (hyperopia or hypermetropia) in two individuals and astigmatism, cerebral visual impairment (CVI), optic atrophy and involuntary eye movements (nystagmus) in one individual each.
Brain imaging anomalies
Among the patients who had an MRI, 40% had abnormalities. These include changes in white matter, prominent ventricles, Chiari malformation, periventricular nodular heterotopia and malrotation of the hippocampus. These changes are not consistent across individuals, although changes in white matter are the most frequently observed.
Seizures
Seizures have been reported in one third of individuals. Epilepsy and staring spells have also been reported.
Movement abnormalities
Changes in movement are reported in 32% of individuals. One individual each has been diagnosed with cerebral palsy, abnormal involuntary (hyperkinetic) movements, slow, halted movements (bradykinesia) or involuntary movements of fingers or toes (choreathetoid movements). Two reported individuals have poor coordination or balance, and two individuals have ataxia.
Genitourinary abnormalities
About one quarter of individuals have genitourinary abnormalities. These include multicystic kidneys, renal agenesis, kidney disease and lack of bladder control (neurogenic bladder). Retractile testes or undescended testes (cryptorchidism) has been reported in a small number of individuals.
Growth delay
Growth delay, primarily short stature, has been observed in 22% of individuals. Feeding issues in infancy have also been reported, including use of a feeding tube.
SYNCRIP-RNDD is caused by pathogenic or likely pathogenic variants in the SYNCRIP (also known as HNRNPQ) gene. Most variants are loss-of-function and result in a nonfunctional protein product that leads to half of the necessary amount of SYNCRIP/hnRNPQ protein for normal cellular function (haploinsufficiency). Missense and insertion/deletion (indel) variants are rarer but have been reported more frequently with increased genomic testing. To date, all variants reported in the medical literature are de novo, which means that they occurred for the first time in the affected person and were not inherited from a parent.
SYNCRIP-RNDD follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause the disease. The risk of passing the altered gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
SYNCRIP-RNDD has been described all over the world and is not population specific.
SYNCRIP-RNDD may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic or likely pathogenic variant in the SYNCRIP gene.
Standard therapies have not been described for SYNCRIP-RNDD. Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.
Developmental delay and intellectual disability should be managed by a developmental pediatrician. Speech and language delay should be managed by appropriate healthcare professionals. Behavioral differences should be managed by appropriate healthcare professionals.
Epilepsy should be treated with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.
Poor weight gain and failure to thrive may require feeding therapy and gastrostomy tube placement for persistent feeding issues.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Brandão-Teles C, Antunes ASLM, de Moraes Vrechi TA, Martins-de-Souza D. The roles of hnRNP family in the brain and brain-related disorders. Mol Neurobiol. Published online November 24, 2023. doi:10.1007/s12035-023-03747-4
Johansson J, Lidéus S, Frykholm C, Gunnarsson C, Mihalic F, Gudmundsson S et al. Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions. Eur J Hum Genet EJHG. 2023. doi:10.1038/s41431-023-01392-y.
Niggl E, Bouman A, Briere LC, Hoogenboezem RM, Wallaard I, Park J et al. HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder. Am J Hum Genet. 2023; 110:1414–1435.
Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H et al. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Med. 2021; 13:1–26.
Semino F, Schröter J, Willemsen MH, Bast T, Biskup S, Beck-Woedl S et al. Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder. Hum Mutat. 2021; 42:1094–1100.
Reichert SC, Li R, Turner SA, Jaarsveld RH van, Massink MPG, Boogaard M-JH van den et al. HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome. Clin Genet. 2020;98: 91–98.
Duijkers FA, McDonald A, Janssens GE, Lezzerini M, Jongejan A, van Koningsbruggen S et al. HNRNPR variants that impair homeobox gene expression drive developmental disorders in humans. Am J Hum Genet. 2019; 104:1040–1059.
Guo H, Duyzend MH, Coe BP, Baker C, Hoekzema K, Gerdts J et al. Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Genet Med Off J Am Coll Med Genet. 2019; 21:1611–1620.
Au PYB, Goedhart C, Ferguson M, Breckpot J, Devriendt K, Wierenga K et al. Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature. Eur J Hum Genet EJHG 2018; 26:1272–1281.
Engwerda A, Frentz B, den Ouden AL, Flapper BCT, Swertz MA, Gerkes EH et al. The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports. Eur J Hum Genet. 2018; 26:1478–1489.
Pilch J, Koppolu AA, Walczak A, Murcia Pienkowski VA, Biernacka A, Skiba P et al. Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation. Clin Genet. 2018; 94:381–385.
Bramswig NC, Lüdecke H-J, Hamdan FF, Altmüller J, Beleggia F, Elcioglu NH et al. Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability. Hum Genet. 2017; 136:821–834.
Yates TM, Vasudevan PC, Chandler KE, Donnelly DE, Stark Z, Sadedin S et al. De novo mutations in HNRNPU result in a neurodevelopmental syndrome. Am J Med Genet A. 2017; 173:3003–3012.
Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C et al. Variants in HNRNPH2 on the X Chromosome are associated with a neurodevelopmental disorder in females. Am J Hum Genet. 2016; 99:728–734.
Lelieveld SH, Reijnders MRF, Pfundt R, Yntema HG, Kamsteeg E-J, de Vries P et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016; 19:1194–1196.
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