Submission Details

FAT4 was first reported in relation to FAT4-related neurodevelopmental disorder in 2013 (Cappello S, et al., 2013, PMID: 24056717). It is caused by mutations in the FAT4 gene, which encodes a protein that is a member of a large family of protocadherins and may play a role in regulating planar cell polarity (PCP) [provided by RefSeq, Mar 2014]. FAT4 is an endothelial cell protein expressed in lymphatic cells that could alter the trafficking of immune cells out of the circulation, and in some cases resulting in secondary lymphopenia due to losses or third-spacing. Mutations in the FAT4 gene are implicated in both Hennekam lymphangiectasia-lymphedema syndrome 2 and Van Maldergem syndrome 2, disorders that are characterized by defects in cell adhesion and planar cell polarity. These disorders share overlapping clinical features and are associated with disruptions in planar cell polarity and cadherin-mediated cell adhesion mechanisms. The clinical presentations vary—Hennekam syndrome tends to present with lymphatic dysplasia, while Van Maldergem syndrome 2 is characterized by craniofacial and limb anomalies. Initially regarded as distinct clinical entities, emerging evidence now supports the concept that these disorders represent variable manifestations within a continuum of developmental abnormalities caused by aberrant FAT4 function. (Betterman KL et al., 2020, PMID:32182215). Affected probands may present with brain malformations including hypoplasia of callosal body, hippocampal malrotation, and periventricular nodular heterotopia. Brain anomalies may be underdiagnosed since not all patients are screened for them. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions suggesting that these may constitute a disease spectrum associated with variants in FAT4. Therefore, the two conditions– Hennekam lymphangiectasia-lymphedema syndrome 2(OMIM:616006) and Van Maldergem syndrome 2 (OMIM:615546), have been lumped into one disease entity– FAT4-related neurodevelopmental disorder.
Fourteen variants that have been reported in 11 probands in 3 publications (Cappello S, et al., 2013, PMID: 24056717; Alders M, et al., 2014, PMID: 24913602; Ivanovski I, et al., 2018, PMID: 29681106), are included in this curation. This gene-disease relationship is also supported by a non-human model organism. The shRNA knockdown mouse model demonstrates phenotypes closely resembling those seen in humans with FAT4, particularly in the form of neuronal heterotopia, abnormal neuroprogenitor proliferation, and disrupted neuronal migration (Cappello S, et al., 2013, PMID: 24056717). In summary, there is definitive evidence to support the relationship between FAT4 and autosomal recessive FAT4-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) GCEP on the meeting date February 20, 2025 (SOP Version 11).

FAT4 was first reported in relation to FAT4-related neurodevelopmental disorder in 2013 (Cappello S, et al., 2013, PMID: 24056717). It is caused by mutations in the FAT4 gene, which encodes a protein that is a member of a large family of protocadherins and may play a role in regulating planar cell polarity (PCP) [provided by RefSeq, Mar 2014]. FAT4 is an endothelial cell protein expressed in lymphatic cells that could alter the trafficking of immune cells out of the circulation, and in some cases resulting in secondary lymphopenia due to losses or third-spacing. Mutations in the FAT4 gene are implicated in both Hennekam lymphangiectasia-lymphedema syndrome 2 and Van Maldergem syndrome 2, disorders that are characterized by defects in cell adhesion and planar cell polarity. These disorders share overlapping clinical features and are associated with disruptions in planar cell polarity and cadherin-mediated cell adhesion mechanisms. The clinical presentations vary—Hennekam syndrome tends to present with lymphatic dysplasia, while Van Maldergem syndrome 2 is characterized by craniofacial and limb anomalies. Initially regarded as distinct clinical entities, emerging evidence now supports the concept that these disorders represent variable manifestations within a continuum of developmental abnormalities caused by aberrant FAT4 function. (Betterman KL et al., 2020, PMID:32182215). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions suggesting that these may constitute a disease spectrum associated with variants in FAT4. Therefore, the two conditions– Hennekam lymphangiectasia-lymphedema syndrome 2(OMIM:616006) and Van Maldergem syndrome 2 (OMIM:615546), have been lumped into one disease entity– FAT4-related neurodevelopmental disorder.
Fourteen variants that have been reported in 11 probands in 3 publications (Cappello S, et al., 2013, PMID: 24056717; Alders M, et al., 2014, PMID: 24913602; Ivanovski I, et al., 2018, PMID: 29681106), are included in this curation. This gene-disease relationship is also supported by a non-human model organism. The shRNA knockdown mouse model demonstrates phenotypes closely resembling those seen in humans with FAT4, particularly in the form of neuronal heterotopia, abnormal neuroprogenitor proliferation, and disrupted neuronal migration (Cappello S, et al., 2013, PMID: 24056717). In summary, there is definitive evidence to support the relationship between FAT4 and autosomal recessive FAT4-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) GCEP on the meeting date February 20, 2025 (SOP Version 11).