Clinical characteristics.

YIF1B-related neurodevelopmental disorder (YIF1B-NDD) is characterized by severe-to-profound developmental delay / intellectual disability with variable motor abnormalities including axial hypotonia, peripheral hypertonia, dystonia, and dyskinesia; absence of speech in most individuals or very limited speech subject to regression; feeding difficulties; seizures; postnatal microcephaly with nonspecific brain MRI abnormalities; and ophthalmologic involvement (strabismus, nystagmus, optic atrophy, and cortical blindness). Some individuals have hypoventilation.

Diagnosis/testing.

The diagnosis of YIF1B-NDD is established in a proband with suggestive findings and biallelic pathogenic variants in YIF1B identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational support; feeding therapy; gastrostomy tube placement if required for persistent feeding issues; standardized treatments for movement disorder and seizures by an experienced neurologist; treatment per ophthalmologist for refractive errors and strabismus; low vision services as needed; consider ventilation therapy when hypoventilation becomes evident; social work and family support.

Surveillance: Monitor developmental progress, educational needs, growth, nutritional status, safety of oral intake, and changes in seizures at each visit; assess for any new manifestations including seizures, changes in tone, movement disorders, or manifestations of central hypoventilation at each visit; ophthalmology evaluation per treating ophthalmologist; behavioral assessment annually.

Genetic counseling.

YIF1B-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a YIF1B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the YIF1B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

YIF1B-related neurodevelopmental disorder (YIF1B-NDD) should be considered in probands with the following clinical, imaging, and family history findings.

Clinical findings

• Severe-to-profound developmental delay; most individuals do not obtain any developmental milestones.
• Severe-to-profound intellectual disability, with no speech development or limited speech with subsequent regression
• Generalized axial hypotonia of infancy and concurrent peripheral hypertonia
• Infant feeding difficulties
• Movement disorders, including dystonia and dyskinesia or tremors
• Epilepsy, varying from myoclonic seizures to generalized tonic-clonic seizures and infantile spasms
• Neurobehavioral/psychiatric manifestations including autism spectrum disorder and anxiety
• Postnatal microcephaly
• Ophthalmologic involvement, including strabismus, nystagmus, optic atrophy, and cortical blindness
• Hypoventilation and ventilation dependency in the presence of brain stem atrophy

Imaging findings on brain MRI. Nonspecific findings include white matter and myelination abnormalities, corpus callosum hypoplasia, cerebellar atrophy and parenchymal volume loss, cerebellar hypoplasia, and pons and brain stem atrophy (see Figure 1).

Figure 1.

T₁- and T₂-weighted brain MRI images of Individuals 1 and 5-8 in sagittal and axial planes. Note the various degrees of cerebral atrophy, cerebellar hypoplasia, thin corpus callosum, and white matter abnormalities. Reproduced with permission from Medico (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of YIF1B-NDD is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in YIF1B identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic YIF1B variants of uncertain significance (or of one known YIF1B pathogenic variant and one YIF1B variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of YIF1B followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

YIF1B-related neurodevelopmental disorder (YIF1B-NDD) is characterized by severe-to-profound developmental delay / intellectual disability with variable motor abnormalities including axial hypotonia, peripheral hypertonia, dystonia, and dyskinesia; absence of speech in most individuals or very limited speech subject to regression; feeding difficulties; seizures; postnatal microcephaly with nonspecific brain MRI abnormalities; and ophthalmologic involvement (strabismus, nystagmus, optic atrophy, and cortical blindness). Some individuals have hypoventilation. To date, 25 individuals have been identified with biallelic pathogenic variants in YIF1B [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay. All individuals with YIF1B-NDD presented with severe-to-profound developmental delay, evident in the first month of life [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. Normal developmental milestones were most often not achieved. Severe axial hypotonia was seen in most affected individuals, with concurrent peripheral hyperreflexia and spasticity. Head control was only achieved in 5/24 individuals, all of whom had biallelic missense variants; individuals with protein-truncating variants did not achieve head control. Likewise, sitting (4/24), standing (2/24), and walking (2/24) were only observed in individuals with YIF1B missense variants. No speech development occurred in individuals with biallelic YIF1B protein-truncating variants (0/18), with limited speech development only in 4/6 individuals with biallelic YIF1B missense variants; subsequent progressive loss of speech was observed in 3/4 individuals. Feeding problems and difficulties in swallowing occurred in 20/24 individuals early in life, often requiring tube feeding.

Intellectual disability. Although for the majority of affected individuals currently no formal IQ testing results are available, based on clinical estimates the level of intellectually disability of all affected individuals is in the severe-to-profound range [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023].

Movement disorders observed in YIF1B-NDD include dystonia and dyskinesia or tremor [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. For those few individuals for which detailed information is available, movement disorders had an onset around age two to three years with the development of choreiform limb movements, which evolved into axial and limb dystonia with dyskinesia by age four to eight years [AlMuhaizea et al 2020]. In those individuals, dystonia was unresponsive to levodopa or carbidopa but partially improved on trihexyphenidyl [AlMuhaizea et al 2020].

Epilepsy. Seizures occurred in 15/23 affected individuals, and included myoclonic, generalized tonic-clonic, and infantile epileptic spasms of variable degrees of severity [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. Most seizures had onset before age two years, with EEGs showing frequent multifocal and epileptiform discharges and abnormal background indicating diffuse dysfunction. For some individuals, seizure control could be achieved using phenobarbital, levetiracetam, and valproate, whereas others presented with medically refractory generalized epilepsy.

Growth. Growth parameters at birth were normal for those individuals for which information is available. Postnatal microcephaly occurred in 16/24 individuals. Currently, information on postnatal growth and weight is sparse, although a few individuals have been reported to present with poor weight gain and growth deficiency [Diaz et al 2020, Sanri et al 2023].

Ophthalmologic involvement included strabismus, nystagmus, and optic atrophy. Cataract or retinal involvement have not been reported. Cortical blindness was reported in one individual.

Central hypoventilation has been observed in 6/19 reported individuals and seems to be correlated with the level of brain stem atrophy [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. At least three individuals became ventilation dependent.

Neurobehavioral/psychiatric manifestations. Autism spectrum disorder and autistic behaviors have been reported in 4/14 individuals [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. Anxiety and aggression have been reported in a single individual [Diaz et al 2020].

Facial features. No consistent recognizable facial features have been reported in individuals affected with YIF1B-NDD [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023] (see Figure 2).

Figure 2.

Images of Individuals 4–7 and 8 at ages 1 year, 27 years, 7.5 years, 11 months, and 4.5 years, respectively. No consistent dysmorphic features were observed. Note the neurologic posture in Individuals 4, 5, and 7. Reproduced with permission from (more...)

Prognosis. Premature death (before age 2 years) has been reported in five individuals, all with protein-truncating variants. The precise cause of death has not been reported.

Three individuals were older than age 25 years (the oldest reported individual was age 37 years) at the time of publication, demonstrating that survival into adulthood is possible [Diaz et al 2020, Medico Salsench et al 2021].

Genotype-Phenotype Correlations

Although the number of reported individuals with YIF1B-NDD is small (n=25) and the overall phenotype of this disorder is profound to severe, the phenotype of individuals with biallelic protein-truncating YIF1B variants tends to be more severe compared to that of individuals with biallelic missense variants [Medico Salsench et al 2021]. Limited developmental milestones – including limited speech development (4/24), head control (5/24), and capacity to sit (4/24), stand (2/24), and walk (2/24) – were only observed in individuals with biallelic missense variants. This might be due to residual activity of YIF1B in those with missense variants compared to protein-truncating variants [Medico Salsench et al 2021].

Prevalence

To date, 25 individuals with YIF1B-NDD have been reported in the medical literature [AlMuhaizea et al 2020, Diaz et al 2020, Medico Salsench et al 2021, Sanri et al 2023]. As expected for an autosomal recessive disorder, the majority of affected individuals are offspring of consanguineous parents, with at least 15 reported individuals having consanguineous parents and homozygous variants. At least two pathogenic variants have been observed recurrently, possibly indicating founder variants: c.598G>T (p.Glu200Ter) has been identified in individuals of Somali descent, and c.186dupT (p.Ala63fs) has been identified in individuals of Arabic descent.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with YIF1B-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to 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

YIF1B-related neurodevelopmental disorder (YIF1B-NDD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a YIF1B pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a YIF1B pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a YIF1B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with YIF1B-NDD are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a YIF1B pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the YIF1B pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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 the parents of affected children.
• It is appropriate to offer YIF1B molecular genetic testing to the reproductive partners of individuals known to be heterozygous for a YIF1B pathogenic variant, particularly if consanguinity is likely.

Prenatal Testing and Preimplantation Genetic Testing

Once the YIF1B pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

YIF1B encodes YIF1B, a transmembrane protein involved in anterograde protein trafficking from the endoplasmic reticulum to the cell membrane and in the architecture and morphology of the Golgi apparatus. Furthermore, YIF1B interacts with the C terminus of the serotonin receptor HTR1A, where it is proposed to play a role in the transient intracellular trafficking and modulation of 5-HT1AR transport to dendrites in the central nervous system [Carrel et al 2008]. In addition, functional analysis has revealed that YIF1B is involved in lysosomal targeting of ABCB9 (also known as TAPL) [Graab et al 2019] and interacts with RAB6A, a recycle trafficking protein [Al Awabdh et al 2012].

Although the precise molecular mechanisms underlying YIF1B-related neurodevelopmental disorder (YIF1B-NDD) are not yet fully elucidated, functional studies point to disturbed function of protein trafficking, dysfunction of the Golgi apparatus, and aberrant protein interactions with abnormal YIF1B [Diaz et al 2020, Medico Salsench et al 2021]. In addition to Golgi dysfunction, endoplasmic reticulum morphology and primary cilium integrity are disturbed in the absence of Yif1b, leading to neuronal reduction, neuronal death, and alterations of myelination of the motor cortex, causing cerebellar atrophy and enlargement of the ventricles in the Yif1b knockout mice [Diaz et al 2020]. In vitro experiments in human cells with mutated YIF1B (due to either protein-truncating or missense variants) show altered subcellular localization and reduced colocalization with known interacting proteins, including TAPL and RAB6A, indicating reduced functionality compared to wild type YIF1B [Medico Salsench et al 2021].

Mechanism of disease causation. Loss of function. The spectrum of YIF1B pathogenic variants is suggestive of loss of function as the underlying disease mechanism, with the majority of currently identified pathogenic variants being biallelic, protein-truncating loss-of-function variants. Missense variants tend to be localized in or close to the transmembrane domains, affecting highly conserved residues, and have been shown to negatively impact YIF1B function.

Author Notes

Dr Tahsin Stefan Barakat is a clinical geneticist and experimental biologist with broad clinical and research interests in neurodevelopmental disorders. The Barakat laboratory aims to decipher novel mechanisms of neurodevelopmental disorders and develop novel therapies based on this knowledge.

Department of Clinical Genetics
Erasmus MC University Medical Center
Rotterdam, the Netherlands
Email: ln.cmsumsare@takarab.t
Web pages:

• www.erasmusmc.nl/en/research/groups/barakat-lab
• ern-ithaca.eu

Dr TS Barakat (ln.cmsumsare@takarab.t) is actively involved in clinical research regarding individuals with YIF1B-NDD and would be happy to communicate with persons who have any questions regarding diagnosis of YIF1B-NDD or other considerations.

Contact Dr TS Barakat to inquire about review of YIF1B variants of uncertain significance.

Acknowledgments

The Barakat lab was supported by the Netherlands Organisation for Scientific Research (ZonMw Veni, grant 91617021; ZonMw Vidi, grant 09150172110002), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018, and acknowledges other ongoing support for rare disease research from Stichting 12q, EpilepsieNL, CURE Epilepsy, Spastic Paraplegia Foundation, Inc, and the Sophia Research Foundation (Stichting Sophia Kinderziekenhuis Fonds). Funding bodies did not have any influence on study design, results, and data interpretation or final manuscript.

Revision History

• 12 September 2024 (sw) Review posted live
• 21 May 2024 (tsb) Original submission

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