Table 2.

Description of characteristic clinical features of FDH diseases and respective studies in possible knockout (KO), transgenic (TG) or knock-in (KI) mouse model(s).

Disease	OMIM	Disease Manifestation	Mouse Model	Model Utility
Aspartyl- glucosaminuria (AGU)	208,400	Lysosomal storage disease with infantile growth spurt, progressive mental retardation in children, abnormalities in the central nervous system and skeleton and connective tissue lesions	AgaKO: recapitulates well lysosomal storage disease, but manifests symptoms only in aged animals [24,25]	Enzyme replacement and gene therapies successfully used in KO model [26,27,28]
Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED)	240,300	Multi-symptomatic endocrinopathy with fungal infections and ectodermal changes	Aire KO: recapitulates autoimmune symptoms of APECED [29,30]
Cartilage hair hypoplasia (CHH)	250,250	Metaphyseal chondrodysplasia, short stature, sparse hair, immune deficiency, gastrointestinal dysfunctions, anemia, increased risk for lymphoma and impaired spermatogenesis	RmrpKO: embryonic lethal [31]
Choroideremia (CHM)	303,100	X-linked progressive degeneration of the retinal pigment epithelium, photoreceptors and choroid leading to vision loss of affected males	Rep1 cKO: conditional knockouts showed the early onset and progressive retinal degeneration, patchy depigmentation of the retinal pigment epithelium and Rab prenylation defects, leading to premature accumulation of deposits in retinal pigment epithelium [32,33]
Lactase deficiency, congenital (CLD)	223,000	Infantile-onset severe diarrhea and failure to thrive	N/A
Ceroid lipofuscinosis, neuronal, 1 (CLN1)	256,730	Infantile-onset, lethal neurodegenerative disease leading to psychomotor deterioration, muscular hypotonia, ataxia, myoclonia, microcephaly, progressive epilepsy and visual impairment causing blindness	Ppt1KO: (exon 9 or exon 4): similar CLN1-like phenotypes with blindness, seizures and myoclonic jerks; progressive motor difficulties leading to hind limb paralysis and death [34,35,36,37,38,39]	Gene therapy testing conducted using the Ppt1 KO mice [24,38,40]
Ceroid lipofuscinosis, neuronal, 3 (CLN3)	204,200	Fatal neurodegenerative disorder with childhood-onset vision impairment, intellectual disability, movement problems, speech difficulties and seizures, which worsen over time	Cln3KO: neuronal storage disorder and other neuropathologies [41] Cln3(Δex7/8) KI: degenerative changes in retina, cerebral cortex and cerebellum; neurological deficits and premature death [40,42]	Although both mouse models recapitulate the aspects of CLN3, they either also show non-neuronal or genetic background-dependent phenotypes, thus not being good models for interventional studies [40,43]
Ceroid lipofuscinosis, neuronal, 5 (CLN5)	256,731	Childhood-onset developmental regression, myoclonic epilepsy, ataxia, vision loss, speech problems and a decline in intellectual function with varied life expectancy	Cln5 KO: progressive pathology of the brain mimics the CLN5 symptoms, and Cln5 deficiency leads to microglial activation, defective myelination and changes in lipid metabolism [44,45]
Cornea plana 2 (cornea plana congenital) (CNA2)	217,300	Congenital visual impairment, reduced curvature and hazy limbus of the cornea, opacities in the corneal stroma and marked corneal arcus at early age	Kera KO: structural alterations recapitulate disease phenotype, but corneal transparency is normal [46]
Finnish congenital nephrosis (CNF)	256,300	Prenatal onset of massive proteinuria, severe steroid- resistant nephrotic syndrome at birth and rapid progression to end-stage renal failure	Nphs1KO: severe proteinuria associated with kidney defects and leading to postnatal lethality [47,48]
Cohen syndrome (COH1)	216,550	Non-progressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, cardiac dysfunction, hyperlaxity of joints and intermittent neutropenia	Vsp13b KO (IMPC)
Diarrhea, secretory chloride, congenital (DIAR1)	214,700	Fetal-onset watery diarrhea, polyhydramnion and chronic diarrhea due to chloride absorption defect	Slc26a3KO: inpenetrant postnatal lethality, and survivors suffer from growth retardation and acidic chloridorrhea [49]
Diastrophic dysplasia (DTD)	222,600	Chondrodysplasia causing severe growth retardation and structural and functional abnormalities of joints	Slc26a2KI (hypomorph): recapitulates essential aspects of DTD such as growth retardation, skeletal dysplasia and joint contractures [50]	Therapeutic approaches to improve skeletal deformity and short stature in DTD successfully tested using Slc26a2 KI mice [51]
Epilepsy, progressive myoclonic, 1 (EPM1)	254,800	Childhood- or juvenile-onset progressive myoclonic epilepsy with variable severity	CstbKO: phenocopies progressive ataxia and myoclonic seizures [52,53]
Epilepsy, progressive, with mental retardation (EPMR)	610,003	A neurodegenerative, lysosomal storage disease characterized by childhood-onset epilepsy and progressive mental retardation	Cln8mnd (267–268insC; frameshift, predicted truncated protein): early onset retinal degeneration and adult-onset hindlimb weakness and ataxia, progressing to spastic paralysis of all limbs and death by 9–14 months; accumulation of intracytoplasmic and lipopigment immunoreactive to ATP synthase subunit c [54,55,56,57] Cln8 KO (IMPC)	Gene therapy testing conducted using Cln8mnd mice [58]
Amyloidosis, Finnish type (FAF)	105,120	Amyloidogenic disease characterized by lattice corneal dystrophy, cranial neuropathy, bulbar signs, and dermatologic changes. Peripheral neuropathy and renal failure are less common symptoms	hGSNTg: transgenic line expressing human D187N gelsolin modeling the pathogenic endoproteolytic cascade that leads to gelsolin amyloidogenic peptides and accumulation with amyloidogenesis is restricted to muscle tissue [59]	Mouse model was used to test D187N gelsolin-targeting nanobodies with positive results [60]
Glycine encephalopathy (GCE)	605,899	Accumulation of glycine in neonates. Disease varies from attenuated to fatal form and presents with lethargy, hypotonia, myoclonic jerks and apneas	GldcKO: neonatal disease features with increased glycine levels, premature lethality and hydrocephalus, in addition to neural tube defects [61]	Abnormalities of folate metabolism and hydrocephalus were prevented by maternal supplementation of carbon donor to normalize folate cycle [62,63]
Gracile syndrome (GRACILE)	603,358	A mitochondrial disease characterized by severe growth retardation, lactic acidosis, nonspecific amino aciduria, cholestasis and abnormalities in iron metabolism, resulting neonatal or early infancy lethality	Bcs1l KI: similar phenotype to human diseases such as growth restriction (>4 wk), progressive liver disease, renal tubulopathy and premature death (<6 wk) [64,65]
Hydrolethalus syndrome 1 (HLS1)	236,680	A lethal condition of fetus with hydramnion and multiple developmental anomalies, including central nervous system malformation, micrognathia, polydactyly, congenital heart defects and abnormal lung lobuli	Hyls1 KO (IMPC)
Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA)	258,870	Hyperornithinemia presumably due to OAT deficiency; triad of progressive chorioretinal degeneration, early cataract formation and type II muscle fiber atrophy; progressive vision loss	OatKO: neonatal hypoornithinemia and lethality rescuable by short-term arginine supplementation; postweaning hyperornithinemia; retinal degeneration in aged mice recapitulating the HOGA phenotype [66]
Imerslund-Grasbeck syndrome 1 (IGS1)	261,100	Infancy- or early childhood-onset proteinuria and megaloblastic anemia due to vitamin B12 (cobalamin, Cbl) deficiency caused by vitamin B12 malabsorption	CubnKO: no disease recapitulation, embryonic lethality [67]
Infantile onset spinocerebellar ataxia (IOSCA)	271,245	Severe progressive neurodegenerative disorder characterized primarily by hypotonia, ataxia, ophthalmoplegia, hearing impairment, epilepsy and sensory axonal neuropathy	C10orf2KI: IOSCA mice manifest a mitochondrial epileptic encephalohepatopathy replicating the key findings of IOSCA patients [68,69]	Suitable model for testing metabolic interventions as treatment options for mitochondrial diseases
Lethal arthrogryposis with anterior horn cell disease (LAAHD)	611,890	Prenatal onset of diminished fetal mobility and contractures and postnatal respiratory failure resulting in perinatal death	Gle1 KO (IMPC)
Lethal congenital contracture syndrome 1 (LCCS1)	253,310	A lethal condition of fetus with lack of movements, hydrops, micrognathia, pulmonary hypoplasia and multiple joint contractures	Gle1 KO (IMPC)
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency *	609,016	A mitochondrial disorder of long-chain fatty acid oxidation characterized by infancy- or early childhood-onset hypoglycemia, metabolic acidosis, hypotonia, liver disease, cardiomyopathy and arrhythmias, as well as a later onset of chronic peripheral neuropathy and pigmentary retinopathy	HadhaKO: embryonic lethality in homozygotes, hepatic steatosis at a young age (3 mo) and hepatocellular carcinoma without cirrhosis at an older age (>13 mo) in heterozygotes [70]
Lysinuric protein intolerance (LPI)	222,700	Inborn error of amino acid metabolism resulting in growth failure, renal disease, hyperammonemia, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis	Slc7a7KO1: growth restriction and very early embryonic lethality [71]
			Slc7a7KO2: deletions do not recapitulate precisely the variants that have been reported in humans; key features of human LPI such as intrauterine growth restriction and proximal tubular dysfunction are present [72]
Muscular dystrophy–dystroglycanopathy (congenital with brain and eye anomalies), type A, 3 (MDDGA3)	253,280	Brain and eye malformations, severe, congenital muscular dystrophy, mental retardation and survival up to more than 70 years	Pomgnt1KO1: viable mice developmental defects in muscle, eye and brain, similar to the phenotypes observed in humans [73,74] Pomgnt1 KO2: increased postnatal lethality, mild dystrophy with reduction in muscle mass and muscle fibers and impaired muscle regeneration [75]
Meckel syndrome type 1, (MKS1)	249,000	Genetically heterogenous disease with the main features being central nervous system malformation, polycystic kidneys, fibrotic changes in the liver, congenital heart malformation and polydactyly	Mks1KO: 259 amino acid deletion resulted in craniofacial defects, polydactyly, congenital heart defects, polycystic kidneys and randomized left-right patterning, quite similar to the human MKS1 phenotype [76]
Mulibrey nanism (MUL)	253,250	Multi-organ disorder with prenatal onset growth failure, cardiomyopathy, characteristic craniofacial features, infertility, insulin resistance with type 2 diabetes and an increased risk for tumors	Trim37KO: recapitulates several features of the multi-organ human disorder, including infertility, increased risk for tumors, fatty liver and cardiomyopathy [77]
Ovarian dysgenesis 1 (ODG1)	233,300	Hypergonadotropic hypogonadism with poorly developed streak ovaries in females and smaller testes and from low to normal sperm counts in men	FshrKO: recapitulates human phenotype quite well; females have small ovaries due to a blockage of folliculogenesis, and male mice have smaller testes and reduced sperm counts [78,79,80]
PEHO syndrome	260,565	Early infancy-onset hypotonia, delayed psychomotor development, infantile spasms, optic atrophy, progressive atrophy of the cerebellum and brainstem, dysmyelination and profound mental retardation	N/A
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (PLOSL1)	221,770	Adult-onset disorder of bones and central nervous system, leading to early dementia and death	TyrobpKO: recapitulates skeletal and psychotic characteristics of PLOSL1 [81]	Promising drug therapy testing conducted using Tyrobp KO mice [82]
RAPADILINO syndrome	266,280	Radial and patellar aplasia, cleft or highly arched palate, diarrhea, dislocated joints, small size and limb malformations, long slender nose, cancer predisposition and normal intelligence	Recql4 ex 5-8 KO: embryonic lethality; Recql4 ex 13 KO: neo- and postnatal lethality with growth retardation, skin, hair and bone defects; Recql4 ex 9-13 KO: palate and limb defects and cancer predisposition [83,84,85]
Retinoschisis (RS1)	312,700	X-linked childhood-onset reduced visual acuity due to retinal dystrophy leading to retinoschisis (splitting) of the neural retina in affected men	Rs1KO: not exactly recapitulating the human phenotype as disrupted organization of the retina was in all cell layers [86]	Successful gene replacement therapy in KO model [87], and dorzolamide treatment improved morphological features in 6 of 7 patients [88]
Salla disease (SD)	604,369	Hypotonia and delayed development in infancy, cerebellar ataxia, progressive cerebellar atrophy and dysmyelination leading to mental retardation; viscero- megaly and coarse features, enlarged lysosomes and high amounts of free sialic acid excreted in the urine	Slc17a5 KO: recapitulates hypomyelinating and lysosomal accumulation phenotype in CNS; in addition to premature death, poor coordination and seizures [89,90]
Tibial muscular dystrophy (TMD)	600,334	Late adult-onset tibial muscular dystrophy	TtnKO: embryonic or postnatal death; Ttn muscle-specific KO: adolescent death [91,92]
Usher syndrome, type III (USH3)	276,902	Post-lingual, progressive hearing loss and loss of central visual acuity later in life	Clrn1KO: phenocopies early onset hearing loss, but not visual impairment [93,94]	Transgene strategy used for possible therapeutic intervention for Usher syndrome [94]

* Currently under consideration for FDH. KO (IMPC): mouse knockout has been generated by the International Mouse Knockout Consortium, and preliminary screening has been performed by the International Mouse Phenotyping Consortium (https://www.mousephenotype.org, accessed on 25 September 2021), but no scientific publication exists yet. CNS: central nervous system; KO: knockout; N/A: not available.